Detailed pathologic analysis has delineated a close association between intratumoral CD 8⁺ cytotoxic T cells and favorable clinical outcomes in diverse cancers. Conversely, the presence at tumor sites of negative immune regulatory elements, such as FoxP 3⁺ T cells (Tregs) and PD‐1/PD‐L1 co‐stimulatory molecules, is closely associated with inferior patient survival. Together, these results indicate the importance of the balance between cytotoxic and regulatory pathways in the tumor microenvironment as a critical determinant of prognosis. This immune index also provides a framework for devising therapeutic strategies to enlarge the population of antitumor cytotoxic T cells and attenuate immune regulation. Among these approaches, vaccination with irradiated, autologous tumor cells engineered to secrete granulocyte–macrophage colony‐stimulating factor (GM‐CSF) followed by antibody blockade of cytotoxic T‐lymphocyte associated antigen‐4 (CTLA‐4) provides clinical benefits for some advanced‐course melanoma patients. The extent of tumor necrosis in post‐treatment biopsies is linearly related to the natural logarithm of the ratio of CD 8⁺ T cells to FoxP 3⁺ Tregs. These findings show a concordance between the immune signature of tumor protection in endogenous and therapy‐induced responses, strongly supporting Martin Mihm's original insights.

Hodi FS, Dranoff G. The biologic importance of tumor‐infiltrating lymphocytes.