Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological “side” effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological “side” effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Cancer is historically conceived as a cell-autonomous disease driven by the activation of (proto)oncogenes or the inactivation of oncosuppressor genes (Hanahan and Weinberg, 2000Hanahan D. Weinberg R.A. The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (16429) Google Scholar). Logically, the ultimate goal of anticancer therapy consists of the destruction of malignant cells. This can be attained with cytotoxic drugs that target rapidly proliferating cells, especially when these cells, like cancer cells, are particularly vulnerable because of aberrations in the mechanisms that control adaptive stress responses and cell death (Fulda et al., 2010Fulda S. Galluzzi L. Kroemer G. Targeting mitochondria for cancer therapy.Nat. Rev. Drug Discov. 2010; 9: 447-464Crossref PubMed Scopus (650) Google Scholar, Solimini et al., 2007Solimini N.L. Luo J. Elledge S.J. Non-oncogene addiction and the stress phenotype of cancer cells.Cell. 2007; 130: 986-988Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Based on their principal mechanism of action, conventional chemotherapeutics can be broadly subdivided into: (1) alkylating agents, which provoke inter- or intra-strand DNA crosslinks that destabilize DNA during replication (e.g., cyclophosphamide); (2) antimetabolites, which inhibit the synthesis of DNA, RNA, or their building blocks (e.g., 5-fluorouracil [5-FU]); (3) topoisomerase inhibitors, which impede the correct unwinding of DNA during replication and transcription (e.g., irinotecan); (4) microtubular poisons, which interfere with the polymerization or depolymerization of tubulin, hence inhibiting the mitotic spindle (e.g., paclitaxel); and (5) cytotoxic antibiotics, which exert antineoplastic effects by various mechanisms, including DNA intercalation and overgeneration of reactive oxygen species (e.g., bleomycin). Alternatively, neoplastic cells can be targeted with molecules that are tailored on cancer-specific alterations (e.g., oncogenic signaling pathways, mechanisms of non-oncogene addiction), a therapeutic paradigm that follows the precepts of “precision medicine” (Werner et al., 2014Werner H.M. Mills G.B. Ram P.T. Cancer Systems Biology: a peek into the future of patient care?.Nat. Rev. Clin. Oncol. 2014; 11: 167-176Crossref PubMed Scopus (0) Google Scholar). The use of both conventional and targeted chemotherapeutics has been successfully implemented in the clinical praxis, seemingly comforting the cell-autonomous perception of cancer that has been driving the development of antineoplastic agents over the past 50 years. Yet another treatment modality recently unveiled a tremendous clinical potential: the so-called immune checkpoint blockers (ICBs) (Lesokhin et al., 2015Lesokhin A.M. Callahan M.K. Postow M.A. Wolchok J.D. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation.Sci. Transl. Med. 2015; 7: 280sr1Crossref PubMed Scopus (0) Google Scholar). No less than three distinct ICBs are currently approved by the US Food and Drug Administration (FDA) and other equivalent agencies worldwide for anticancer therapy: (1) ipilimumab (Yervoy), a monoclonal antibody (mAb) blocking cytotoxic T lymphocyte-associated protein 4 (CTLA4), which is licensed for use in patients with unresectable or metastatic melanoma; (2) pembrolizumab (Keytruda), an mAb blocking programmed cell death 1 (PDCD1, best known as PD-1), which is approved for use in individuals with unresectable or metastatic melanoma experiencing disease progression on ipilimumab or targeted anticancer agents; and (3) nivolumab (Opdivo), a PD-1-targeting mAb licensed for use in subjects with unresectable or metastatic melanoma that no longer responds to other drugs, as well as in patients with advanced or metastatic non-small cell lung carcinoma (NSCLC) progressing on or after platinum-based chemotherapy (Lesokhin et al., 2015Lesokhin A.M. Callahan M.K. Postow M.A. Wolchok J.D. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation.Sci. Transl. Med. 2015; 7: 280sr1Crossref PubMed Scopus (0) Google Scholar). These and other ICBs are expected to obtain regulatory approval for an expanding panel of oncological indications based on impressive results from several, randomized clinical studies (Ansell et al., 2015Ansell S.M. Lesokhin A.M. Borrello I. Halwani A. Scott E.C. Gutierrez M. Schuster S.J. Millenson M.M. Cattry D. Freeman G.J. et al.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.N. Engl. J. Med. 2015; 372: 311-319Crossref PubMed Google Scholar, Westin et al., 2014Westin J.R. Chu F. Zhang M. Fayad L.E. Kwak L.W. Fowler N. Romaguera J. Hagemeister F. Fanale M. Samaniego F. et al.Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial.Lancet Oncol. 2014; 15: 69-77Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). The clinical success of ICBs demonstrates that cancer can be efficiently treated by targeting immune, rather than malignant, cells, spurring renovated interest in the immunosurveillance theory. According to this concept, tumors can only originate and progress in the context of failing immune responses (Schreiber et al., 2011Schreiber R.D. Old L.J. Smyth M.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion.Science. 2011; 331: 1565-1570Crossref PubMed Scopus (1589) Google Scholar, Zitvogel et al., 2006Zitvogel L. Tesniere A. Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion.Nat. Rev. Immunol. 2006; 6: 715-727Crossref PubMed Scopus (672) Google Scholar). This implies that (one of) the goal(s) of cancer therapy should consist in reinstating the immunological control of tumor growth (Schreiber et al., 2011Schreiber R.D. Old L.J. Smyth M.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion.Science. 2011; 331: 1565-1570Crossref PubMed Scopus (1589) Google Scholar, Zitvogel et al., 2006Zitvogel L. Tesniere A. Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion.Nat. Rev. Immunol. 2006; 6: 715-727Crossref PubMed Scopus (672) Google Scholar). Thus, the mechanistic rationale behind the development of anticancer immunotherapies is completely different from that subjacent to conventional and targeted antineoplastic agents. Preclinical and clinical data accumulating over the past decade have begun to erode the frontiers between a purely cell-autonomous and a purely immunological approach to the development of anticancer drugs. For instance, it became clear that the density, composition, localization, and function of tumor-infiltrating lymphoid and myeloid cells, the so-called immune contexture, has a major prognostic and predictive value in patients with cancer treated with conventional or targeted anticancer agents (Table 1) (Fridman et al., 2012Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. The immune contexture in human tumours: impact on clinical outcome.Nat. Rev. Cancer. 2012; 12: 298-306Crossref PubMed Scopus (897) Google Scholar). Thus, the immune contexture determined at diagnosis influences the prognosis of individuals affected by virtually all solid neoplasms, including colorectal carcinoma (Anitei et al., 2014Anitei M.G. Zeitoun G. Mlecnik B. Marliot F. Haicheur N. Todosi A.M. Kirilovsky A. Lagorce C. Bindea G. Ferariu D. et al.Prognostic and predictive values of the immunoscore in patients with rectal cancer.Clin. Cancer Res. 2014; 20: 1891-1899Crossref PubMed Scopus (63) Google Scholar), breast carcinoma (Ascierto et al., 2013Ascierto P.A. Capone M. Urba W.J. Bifulco C.B. Botti G. Lugli A. Marincola F.M. Ciliberto G. Galon J. Fox B.A. The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment.J. Transl. Med. 2013; 11: 54Crossref PubMed Scopus (0) Google Scholar), NSCLC (Remark et al., 2015Remark R. Becker C. Gomez J.E. Damotte D. Dieu-Nosjean M.C. Sautès-Fridman C. Fridman W.H. Powell C.A. Altorki N.K. Merad M. Gnjatic S. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome.Am. J. Respir. Crit. Care Med. 2015; 191: 377-390Crossref PubMed Scopus (30) Google Scholar), ovarian carcinoma (Nelson, 2015Nelson B.H. New insights into tumor immunity revealed by the unique genetic and genomic aspects of ovarian cancer.Curr. Opin. Immunol. 2015; 33: 93-100Crossref PubMed Google Scholar), and prostate cancer (Ness et al., 2014Ness N. Andersen S. Valkov A. Nordby Y. Donnem T. Al-Saad S. Busund L.T. Bremnes R.M. Richardsen E. Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer.Prostate. 2014; 74: 1452-1461Crossref PubMed Google Scholar). Moreover, it turned out that widely used conventional chemotherapeutics as well as target anticancer agents modulate the composition and functionality of the tumor infiltrate, and this affects disease outcome (Senovilla et al., 2012aSenovilla L. Vacchelli E. Galon J. Adjemian S. Eggermont A. Fridman W.H. Sautès-Fridman C. Ma Y. Tartour E. Zitvogel L. et al.Trial watch: Prognostic and predictive value of the immune infiltrate in cancer.OncoImmunology. 2012; 1: 1323-1343Crossref PubMed Scopus (105) Google Scholar). Thus, an increased amount of intratumoral immune effectors (alone or coupled to a decreased abundance of immunosuppressive cells) in response to treatment was shown to correlate with pathological complete response as well as progression-free and overall survival in patients with breast carcinoma treated with anthracycline- or taxane-based neoadjuvant chemotherapy (Issa-Nummer et al., 2013Issa-Nummer Y. Darb-Esfahani S. Loibl S. Kunz G. Nekljudova V. Schrader I. Sinn B.V. Ulmer H.U. Kronenwett R. Just M. et al.Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial.PLoS ONE. 2013; 8: e79775Crossref PubMed Google Scholar, Senovilla et al., 2012bSenovilla L. Vitale I. Martins I. Tailler M. Pailleret C. Michaud M. Galluzzi L. Adjemian S. Kepp O. Niso-Santano M. et al.An immunosurveillance mechanism controls cancer cell ploidy.Science. 2012; 337: 1678-1684Crossref PubMed Scopus (155) Google Scholar). Similarly, the tyrosine kinase inhibitor (TKI) imatinib mesylate (see below) was shown to increase the abundance of CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells within gastrointestinal stromal tumors (GISTs), and this correlated with disease outcome (Rusakiewicz et al., 2013Rusakiewicz S. Semeraro M. Sarabi M. Desbois M. Locher C. Mendez R. Vimond N. Concha A. Garrido F. Isambert N. et al.Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.Cancer Res. 2013; 73: 3499-3510Crossref PubMed Scopus (0) Google Scholar). Genetic and epigenetic determinants of the functionality of circulating and tumor-infiltrating NK cells also affect the prognosis of GIST patients treated with imatinib (Delahaye et al., 2011Delahaye N.F. Rusakiewicz S. Martins I. Ménard C. Roux S. Lyonnet L. Paul P. Sarabi M. Chaput N. Semeraro M. et al.Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.Nat. Med. 2011; 17: 700-707Crossref PubMed Scopus (136) Google Scholar), corroborating the notion that the therapeutic effects of targeted anticancer agents rely (at least in part) on the (re)activation of a tumor-targeting immune response. Preclinical data obtained in mice in which distinct immune effectors were ablated or, on the contrary, specific immunosuppressive circuits were inactivated demonstrate that many chemotherapeutic agents that were initially developed according to a purely cancer cell-autonomous logics mediate antineoplastic effects via immunological mechanisms (Galluzzi et al., 2012Galluzzi L. Senovilla L. Zitvogel L. Kroemer G. The secret ally: immunostimulation by anticancer drugs.Nat. Rev. Drug Discov. 2012; 11: 215-233Crossref PubMed Scopus (289) Google Scholar, Zitvogel et al., 2013Zitvogel L. Galluzzi L. Smyth M.J. Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance.Immunity. 2013; 39: 74-88Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar).Table 1Positive and Negative Impact of Immune Cells on Disease Outcome in Cancer Patients Treated with ChemotherapyCellsMarkersCancer TypeTherapyImpactReferenceB cellsCD20+biliary tract canceradjuvant multimodal chemotherapyrobust tumor infiltration by B cells correlated with improved OSGoeppert et al., 2013Goeppert B. Frauenschuh L. Zucknick M. Stenzinger A. Andrulis M. Klauschen F. Joehrens K. Warth A. Renner M. Mehrabi A. et al.Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer.Br. J. Cancer. 2013; 109: 2665-2674Crossref PubMed Scopus (0) Google Scholarcolorectal carcinomaadjuvant multimodal chemotherapyrobust tumor infiltration by B cells correlated with worsened OSKasajima et al., 2010Kasajima A. Sers C. Sasano H. Jöhrens K. Stenzinger A. Noske A. Buckendahl A.C. Darb-Esfahani S. Müller B.M. Budczies J. et al.Down-regulation of the antigen processing machinery is linked to a loss of inflammatory response in colorectal cancer.Hum. Pathol. 2010; 41: 1758-1769Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholarmelanomaadjuvant IFN-α2b, alone or combined with dacarbazine or temozolomidehigh intratumoral levels of B cells correlated with short OSNeagu et al., 2013Neagu M. Constantin C. Zurac S. Immune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations.BioMed Res. Int. 2013; 2013: 107940Crossref PubMed Scopus (0) Google ScholarCirculating T cellsCD4+melanomaneoadjuvant dacarbazinehigh CD4+ cells or low TREG cells in the peripheral blood correlated with response to treatmentMignot et al., 2014Mignot G. Hervieu A. Vabres P. Dalac S. Jeudy G. Bel B. Apetoh L. Ghiringhelli F. Prospective study of the evolution of blood lymphoid immune parameters during dacarbazine chemotherapy in metastatic and locally advanced melanoma patients.PLoS ONE. 2014; 9: e105907Crossref PubMed Scopus (0) Google ScholarFOXP3+CD4+melanomaadjuvant IFN-α2b, alone or combined with dacarbazine or temozolomidehigh CD4+/CD8+ T cell ratio in the peripheral blood correlated with prolonged OSNeagu et al., 2013Neagu M. Constantin C. Zurac S. Immune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations.BioMed Res. Int. 2013; 2013: 107940Crossref PubMed Scopus (0) Google ScholarCD8+CTLsCD3 mRNAoropharyngeal carcinomaadjuvant chemoradiationhigh levels of CD3 and CD8A predicted improved DFS and OSJung et al., 2013Jung A.C. Guihard S. Krugell S. Ledrappier S. Brochot A. Dalstein V. Job S. de Reynies A. Noël G. Wasylyk B. et al.CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis.Int. J. Cancer. 2013; 132: E26-E36Crossref PubMed Scopus (32) Google ScholarCD8A mRNACD3+/CD8+ovarian carcinomaadjuvant carboplatin- or taxane-based chemotherapyhigh levels of tumor-infiltrating CTLs correlated with improved OSHan et al., 2008Han L.Y. Fletcher M.S. Urbauer D.L. Mueller P. Landen C.N. Kamat A.A. Lin Y.G. Merritt W.M. Spannuth W.A. Deavers M.T. et al.HLA class I antigen processing machinery component expression and intratumoral T-Cell infiltrate as independent prognostic markers in ovarian carcinoma.Clin. Cancer Res. 2008; 14: 3372-3379Crossref PubMed Scopus (84) Google ScholarCD3+/CD8+rectal carcinomaneoadjuvant chemoradiationtumor infiltration by CTLs predicted improved DFS and OSAnitei et al., 2014Anitei M.G. Zeitoun G. Mlecnik B. Marliot F. Haicheur N. Todosi A.M. Kirilovsky A. Lagorce C. Bindea G. Ferariu D. et al.Prognostic and predictive values of the immunoscore in patients with rectal cancer.Clin. Cancer Res. 2014; 20: 1891-1899Crossref PubMed Scopus (63) Google ScholarCD8+ductal breast carcinomaadjuvant multimodal chemotherapyincreased tumor infiltration by CTLs correlated with improved TTR and OSMohammed et al., 2013Mohammed Z.M. Going J.J. Edwards J. Elsberger B. McMillan D.C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer.Br. J. Cancer. 2013; 109: 1676-1684Crossref PubMed Scopus (30) Google ScholarCTLs TREG cellsCD8+breast carcinomaneoadjuvant anthracycline-based chemotherapyincreased intratumoral CTL/TREG cell ratio predicted pCRLadoire et al., 2011Ladoire S. Mignot G. Dabakuyo S. Arnould L. Apetoh L. Rébé C. Coudert B. Martin F. Bizollon M.H. Vanoli A. et al.In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival.J. 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Madden S.F. Gallagher W.M. Wadhwani N. Keil S.D. Junaid S.A. et al.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.Cancer Discov. 2011; 1: 54-67Crossref PubMed Scopus (531) Google Scholargastric carcinomaadjuvant 5-FU-based chemotherapyincreased levels of TAMs correlated with prolonged OSWang et al., 2011Wang B. Xu D. Yu X. Ding T. Rao H. Zhan Y. Zheng L. Li L. Association of intra-tumoral infiltrating macrophages and regulatory T cells is an independent prognostic factor in gastric cancer after radical resection.Ann. Surg. Oncol. 2011; 18: 2585-2593Crossref PubMed Scopus (0) Google Scholarpancreatic adenocarcinomaadjuvant gemcitabine-based chemotherapyhigh levels of peritumoral TAMs predicted response to therapyDi Caro et al., 2015Di Caro G. Cortese N. Castino G.F. Grizzi F. Gavazzi F. Ridolfi C. Capretti G. Mineri R. Todoric J. Zerbi A. et al.Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy.Gut. 2015; https://doi.org/10.1136/gutjnl-2015-309193Crossref PubMed Scopus (10) Google ScholarHEductal breast carcinomaadjuvant multimodal chemotherapytumor infiltration by macrophages predicted improved TTR and OSMohammed et al., 2013Mohammed Z.M. Going J.J. Edwards J. Elsberger B. McMillan D.C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer.Br. J. Cancer. 2013; 109: 1676-1684Crossref PubMed Scopus (30) Google ScholarMyeloid cellsCD16+colorectal carcinomaadjuvant multimodal chemotherapyincreased levels of CD16+ cells correlated with prolonged OSSconocchia et al., 2011Sconocchia G. Zlobec I. Lugli A. Calabrese D. Iezzi G. Karamitopoulou E. Patsouris E.S. Peros G. Horcic M. Tornillo L. et al.Tumor infiltration by FcγRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma.Int. J. Cancer. 2011; 128: 2663-2672Crossref PubMed Scopus (0) Google ScholarNeutrophilsHEductal breast carcinomaadjuvant multimodal chemotherapyhigh intratumoral levels of neutrophils correlated with worsened TTR and OSMohammed et al., 2013Mohammed Z.M. Going J.J. Edwards J. Elsberger B. McMillan D.C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer.Br. J. Cancer. 2013; 109: 1676-1684Crossref PubMed Scopus (30) Google ScholarNK cellsNCR1+GISTadjuvant imatinib-based chemotherapyhigh intratumoral levels of NK cells correlated with prolonged PFSRusakiewicz et al., 2013Rusakiewicz S. Semeraro M. Sarabi M. Desbois M. Locher C. Mendez R. Vimond N. Concha A. Garrido F. Isambert N. et al.Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.Cancer Res. 2013; 73: 3499-3510Crossref PubMed Scopus (0) Google ScholarNK cellsGZMB+Hodgkin lymphomaradiotherapy and optional chemotherapylow intratumoral FOXP3+/GZMB+ cell ratio correlated with shortened RFS and OSKelley et al., 2007Kelley T.W. Pohlman B. Elson P. Hsi E.D. The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression.Am. J. Clin. Pathol. 2007; 128: 958-965Crossref PubMed Scopus (0) Google ScholarCTLsFOXP3+TREG cellsPlasma cellsCD138+ductal breast carcinomaadjuvant multimodal chemotherapyhigh intratumoral levels of plasma cells correlated with worsened TTR and OSMohammed et al., 2013Mohammed Z.M. Going J.J. Edwards J. Elsberger B. McMillan D.C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer.Br. J. Cancer. 2013; 109: 1676-1684Crossref PubMed Scopus (30) Google Scholarmelanomaadjuvant IFN-α2b, alone or combined with dacarbazine or temozolomideincreased tumor infiltration by plasma cells correlated with shortened OSNeagu et al., 2013Neagu M. Constantin C. Zurac S. Immune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations.BioMed Res. Int. 2013; 2013: 107940Crossref PubMed Scopus (0) Google ScholarTH1 cellsTBX21+pancreatic carcinomaAdjuvant chemoradiationincreased intratumoral TH2/TH1 cell ratio correlated with shortened OSDe Monte et al., 2011De Monte L. Reni M. Tassi E. Clavenna D. Papa I. Recalde H. Braga M. Di Carlo V. Doglioni C. Protti M.P. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer.J. Exp. Med. 2011; 208: 469-478Crossref PubMed Scopus (212) Google ScholarTH2 cellsGATA3+TILsCD3+breast carcinomaneoadjuvant chemotherapyincreased amounts of TILs predicted pCRDenkert et al., 2010Denkert C. Loibl S. Noske A. Roller M. Müller B.M. Komor M. Budczies J. Darb-Esfahani S. Kronenwett R. Hanusch C. et al.Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.J. Clin. Oncol. 2010; 28: 105-113Crossref PubMed Scopus (517) Google ScholarGISTadjuvant imatinib-based chemotherapyhigh levels of TILs correlated with improved PFSRusakiewicz et al., 2013Rusakiewicz S. Semeraro M. Sarabi M. Desbois M. Locher C. Mendez R. Vimond N. Concha A. Garrido F. Isambert N. et al.Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.Cancer Res. 2013; 73: 3499-3510Crossref PubMed Scopus (0) Google Scholarmelanomaadjuvant IFN-α2b, alone or combined with dacarbazine or temozolomideincreased amounts of TILs correlated with prolonged OSNeagu et al., 2013Neagu M. Constantin C. Zurac S. Immune parameters in the prognosis and therapy monitoring of cutaneous melanoma patients: experience, role, and limitations.BioMed Res. Int. 2013; 2013: 107940Crossref PubMed Scopus (0) Google Scholarrectal carcinomaneoadjuvant chemoradiationimmunoscore correlated with improved DFS and OSAnitei et al., 2014Anitei M.G. Zeitoun G. Mlecnik B. Marliot F. Haicheur N. Todosi A.M. Kirilovsky A. Lagorce C. Bindea G. Ferariu D. et al.Prognostic and predictive values of the immunoscore in patients with rectal cancer.Clin. Cancer Res. 2014; 20: 1891-1899Crossref PubMed Scopus (63) Google ScholarCD3+melanomaneoadjuvant and/or adjuvant chemotherapyhigh levels of CD3+ and CD8+ cells around metastases correlated with improved OSHamilton et al., 2013Hamilton R. Krauze M. Romkes M. Omolo B. Konstantinopoulos P. Reinhart T. Harasymczuk M. Wang Y. Lin Y. Ferrone S. et al.Pathologic and gene expression features of metastatic melanomas to the brain.Cancer. 2013; 119: 2737-2746Crossref PubMed Scopus (0) Google ScholarCD8+CD4+breast carcinomaneoadjuvant paclitaxel-based chemotherapyhigh CD8+ or low CD4+ T cells within neoplastic lesions correlated with improved RFS and OSDeNardo et al., 2011DeNardo D.G. Brennan D.J. Rexhepaj E. Ruffell B. Shiao S.L. Madden S.F. Gallagher W.M. Wadhwani N. Keil S.D. Junaid S.A. et al.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.Cancer Discov. 2011; 1: 54-67Crossref PubMed Scopus (531) Google ScholarCD8+colorectal carcinomaadjuvant multimodal chemotherapyhigh levels of TILs correlated with improved OSKasajima et al., 2010Kasajima A. Sers C. Sasano H. Jöhrens K. Stenzinger A. Noske A. Buckendahl A.C. Darb-Esfahani S. Müller B.M. Budczies J. et al.Down-regulation of the antigen processing machinery is linked to a loss of inflammatory response in colorectal cancer.Hum. Pathol. 2010; 41: 1758-1769Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarCD4+biliary tract canceradjuvant multimodal chemotherapyhigh levels of TILs correlated with improved OSGoeppert et al., 2013Goeppert B. Frauenschuh L. Zucknick M. Stenzinger A. Andrulis M. Klauschen F. Joehrens K. Warth A. Renner M. Mehrabi A. et al.Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer.Br. J. Cancer. 2013; 109: 2665-2674Crossref PubMed Scopus (0) Google ScholarCD8+FOXP3+CD8+ER+ breast carcinomahormonotherapy plus chemotherapyincreased amounts of TILs correlated with high tumor gradeTsang et al., 2014Tsang J.Y. Hui S.W. Ni Y.B. Chan S.K. Yamaguchi R. Kwong A. Law B.K. Tse G.M. Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers.Breast Cancer Res. Treat. 2014; 143: 1-9Crossref PubMed Scopus (0) Google ScholarFOXP3+ERBB2+ER− breast cancerhormonotherapy plus chemotherapyincreased amounts of TILs correlated with low gradeTsang et al., 2014Tsang J.Y. Hui S.W. Ni Y.B. Chan S.K. Yamaguchi R. Kwong A. Law B.K. Tse G.M. Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers.Breast Cancer Res. Treat. 2014; 143: 1-9Crossref PubMed Scopus (0) Google ScholarHEbreast carcinomaneoadjuvant chemotherapyincreased levels of stromal TILs predicted pCRDenkert et al., 2015Denkert C. von Minckwitz G. Brase J.C. Sinn B.V. Gade S. Kronenwett R. Pfitzner B.M. Salat C. Loi S. Schmitt W.D. et al.Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.J. Clin. Oncol. 2015; 33: 983-991Crossref PubMed Scopus (168) Google Scholarductal breast carcinomaadjuvant multimodal chemotherapyhigh levels of TILs correlated with improved TTR and OSMohammed et al., 2013Mohammed Z.M. Going J.J. Edwards J. Elsberger B. McMillan D.C. The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer.Br. J. Cancer. 2013; 109: 1676-1684Crossref PubMed Scopus (30) Google ScholarTREG cellsFOXP3+cutaneous T cell lymphomanot availablehigh intratumoral levels of TREG cells correlated with low disease stage and improved OSGjerdrum et al., 2007Gjerdrum L.M. Woetmann A. Odum N. Burton C.M. Rossen K. Skovgaard G.L