Cytokine-based cancer immunotherapies induce differential effects on CD4+ and CD8+ T cell phenotype and function

We have recently observed that cytokine-based immunotherapy (IT) regimens induced an Ag-nonspecific expansion of the memory T cell pool which was responsible for anti-tumor efficacy. We therefore sought to determine the effects of systemic IT on subsequent Ag-specific responses. During IT, there was a significant expansion of the memory CD8 T cell population with the cells in active cell cycle. Splenocytes from treated mice proliferated less in response to TCR engagement, yet they proliferated to a greater extent when stimulated with IL2 alone. Flow cytometric analysis of stimulated splenocytes revealed that CD8 T cells from IT treated mice appropriately upregulated activation markers (ie, CD25, CD44, NKG2D) and expanded normally. Conversely, CD4 T cells from the same mice exhibited markedly less proliferation, activation marker upregulation, and IFNγ production in response to the same stimuli. In a vaccine model where mice were immunized against allogeneic splenocytes while undergoing IT, CD8 T cells were capable of responding to antigen earlier and more robustly upon secondary in vitro restimulation than immunized, untreated mice. Together, these data show that immune stimulatory therapies allow CD8 T cells to function as Ag-specific or nonspecific effectors while functionally exhausting CD4 T cells. We also show that neither CD4 exhaustion after IT, nor the nonspecific expansion of memory CD8 T cells impairs the ability of CD8 T cells to generate new Ag-specific responses.