The biologic importance of tumor-infiltrating lymphocytes

Abstract

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.

Figure 1

The ratio of tumor-infiltrating CD8⁺ T cells to FoxP3⁺ Tregs following administration of GM-CSF-secreting melanoma vaccines and anti-CTLA-4 antibody infusion is tightly correlated with the extent of tumor necrosis in advanced melanoma patients. (A). Top, minimal necrosis of melanoma metastasis; bottom, extensive necrosis of melanoma metastasis. (Magnification: H&E ×4; CD8, ×20; FoxP3, ×40.) (B). Numbers of intra-tumoral FoxP3⁺ Tregs and CD8⁺ T cells versus tumor necrosis. Reprinted from (69)