The role of CD4+ tumor-infiltrating lymphocytes in human solid tumors

Many, if not all, solid tumors are characterized by a T cell infiltrate, usually consisting of CD4+ and CD8+ T cells. Characterization of both subsets of tumor-infiltrating lymphocytes (TIL) have shown that each population can be divided into tumor-specific and tumor-nonspecific T cells. A small proportion of tumor-specific CD4+ TIL can directly lyse tumor cells in an HLA class I- or II-restricted fashion. The majority of tumor-specific CD4+ TIL, however, recognize tumor antigens presented on HLA class II molecules by antigen-presenting cells (APC). At the same time, APC in the tumor environment express elevated levels of heat shock antigen (Hsp) 70 (and perhaps other antigens) that can be specifically recognized by tumor-nonspecific CD4+ TIL when presented by HLA class II. Functionally, CD4+ T cells can be distinguished into Th0 (production of IL-2, IL-4, and IFN-gamma), Th1 (IL-2 and IFN-gamma), and Th2 (IL-4). In addition, stressed CD4+ TIL have the ability to produce the growth factors heparin binding epidermal growth factor and basic fibroblast growth factor that support tumor growth. Since the efficacy of an antitumor immune response is codetermined by the net effect of stimulatory and inhibitory cytokines, a detailed understanding of the developmental pathways of CD4+ TIL subsets and their interactions is critical for the design of clinical protocols.