Immunity beyond cancer cells: perspective from tumor tissue

Clonal expansion is necessary but not sufficient for malignant cell transformation, and the cancerous cell phenotype is conditional on a supportive tumor microenvironment. Current immunotherapy approaches are centric on CD8+ cytotoxic T lymphocyte-mediated cancer cell killing with efficacy constrained by primary and acquired resistance mechanisms. CD4+ helper T (Th) cells orchestrate immune defense responses by targeting cancer cells and the cancer environment. Th2 cells can be mobilized as tissue-level anticancer effectors by promoting tumor stroma reconfiguration. Investigation of cancer as a cell-level disease has led to the development of cancer cell-directed therapies including cytotoxic T lymphocyte (CTL)-based immunotherapy; yet, many patients are refractory to these modalities of cancer treatment and acquired resistance frequently occurs. Of note, cancer environment controls the manifestation of cancerous cell phenotype. Helper T (Th) cells orchestrate immune defense responses targeting cancer cells as well as the tumor microenvironment. Recent studies have shown that in addition to interferon (IFN)-γ-producing Th1 cells, interleukin (IL)-4-producing Th2 cells function as potent anticancer effectors in part by promoting tumor stroma reconfiguration and tumor tissue repair. Such Th cell-mediated tissue-level immunity may be harnessed for novel modalities of cancer environment immunotherapy. Investigation of cancer as a cell-level disease has led to the development of cancer cell-directed therapies including cytotoxic T lymphocyte (CTL)-based immunotherapy; yet, many patients are refractory to these modalities of cancer treatment and acquired resistance frequently occurs. Of note, cancer environment controls the manifestation of cancerous cell phenotype. Helper T (Th) cells orchestrate immune defense responses targeting cancer cells as well as the tumor microenvironment. Recent studies have shown that in addition to interferon (IFN)-γ-producing Th1 cells, interleukin (IL)-4-producing Th2 cells function as potent anticancer effectors in part by promoting tumor stroma reconfiguration and tumor tissue repair. Such Th cell-mediated tissue-level immunity may be harnessed for novel modalities of cancer environment immunotherapy.