Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells

CD4(+) T cells enhance tumor destruction by CD8(+) T cells. One benefit that underlies CD4(+) T cell help is enhanced clonal expansion of newly activated CD8(+) cells. In addition, tumor-specific CD4(+) help is also associated with the accumulation of greater numbers of CD8(+) T cells within the tumor. Whether this too is attributable to the effects of help delivered to the CD8(+) cells during priming within secondary lymphoid tissues, or alternatively is due to the action of CD4(+) cells within the tumor environment has not been examined. In this study, we have evaluated separately the benefits of CD4(+) T cell help accrued during priming of tumor-specific CD8(+) T cells with a vaccine, as opposed to the benefits delivered by the presence of cognate CD4(+) cells within the tumor. The presence of CD4(+) T cell help during priming increased clonal expansion of tumor-specific CD8(+) T cells in secondary lymphoid tissue; however, CD8(+) T cells that have low avidity for tumor Ag were inefficient in tumor invasion. CD4(+) T cells that recognized tumor Ag were required to facilitate accumulation of CD8(+) T cells within the tumor and enhance tumor lysis during the acute phase of the response. These experiments highlight the ability of tumor-specific CD4(+) T cells to render the tumor microenvironment receptive for CD8(+) T cell immunotherapy, by facilitating the accumulation of all activated CD8(+) T cells, including low-avidity tumor-specific and noncognate cells.