The biologic importance of tumor-infiltrating lymphocytes.
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
F Stephen
FS
Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA.
Dranoff
Glenn
G
D015703:Antigens, CD / Q000276:immunology; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor