UCSF

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. Even as our ability to isolate and assay individual immune components from the tumor microenvironment (TME) has improved, the immunological features that dictate therapeutic success or failure are poorly understood. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the TME and its influence on response to therapy. As cancer treatments move away from broadly eliminating dividing cells to specifically activating components of the immune system within the TIME, our understanding of the cell types critical for eliciting antitumor responses must be better understood.

Just as tumors can been subcategorized based on pathological and genetic features, categorizing tumors based on their TIME is equally informative. Specific combinations of immune populations within TIME can be highly predictive of both survival and response to immunotherapy. Antigen presenting cells (APCs), and in particular dendritic cells (DC), are emerging as critical components of a responsive TIME. DC have long been recognized for their exquisite ability to bridge detection of a harmful pathogen or virus with the activation of an adaptive T cell response. More recent work from our lab and others has highlighted the function that specific DC populations have in activating CD8+ T cells within the tumor-draining lymph node (tdLN) and tumor. However, CD4+ conventional T cells (Tconv) are emerging as critical partners for productive antitumor responses, but the conditions required for effective CD4+ Tconv activation remain poorly understood.

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) are critical for productive antitumor responses yet their elicitation remains poorly understood. We exhaustively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice their abundance relative to Treg predicts protective ICOShi PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway which restrains cDC2, and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.