Anti-PD-1 therapy triggers Tfh cell-dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes.

Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh).

Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4 CAR T-cell antitumor activity.

CD4 T cells and CD4 chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4 T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4 CAR T cells. Mechanistically, mouse or human CD4 CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants.

Dynamic CD8 T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy.

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks.

Local IFNα enhances the anti-tumoral efficacy of systemic anti-PD1 to prevent tumor relapse.

Background: Tumor relapse constitutes a major challenge for anti-tumoral treatments, including immunotherapies. Indeed, most cancer-related deaths occur during the tumor relapse phase.

Methods: We designed a mouse model of tumor relapse in which mice transplanted with E7 TC1 tumor cells received a single therapeutic vaccination of STxB-E7+IFNα.

Preclinical murine tumor models: a structural and functional perspective.

The goal of this review is to pinpoint the specific features, including the weaknesses, of various tumor models, and to discuss the reasons why treatments that are efficient in murine tumor models often do not work in clinics. In a detailed comparison of transplanted and spontaneous tumor models, we focus on structure-function relationships in the tumor microenvironment. For instance, the architecture of the vascular tree, which depends on whether tumor cells have gone through epithelial-mesenchymal transition, is determinant for the extension of the spontaneous necrosis, and for the intratumoral localization of the immune infiltrate.

TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors.

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors.

The Remarkable Plasticity of Macrophages: A Chance to Fight Cancer.

It is well established that tumor-associated macrophages (TAM) found in most advanced tumors have a pro-tumoral role. In this context, TAM limit the activity of tumor-infiltrating lymphocytes (TIL), and a number of mechanisms have been described including a trapping in the stroma, impeding TIL to reach malignant cells. Based on these results, a number of therapeutic approaches have been designed to deplete TAM.

Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment.

In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices.

The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression.

Regressing tumors are usually associated with a large immune infiltrate, but the molecular and cellular interactions that govern a successful anti-tumor immunity remain elusive. Here, we have triggered type I Interferon (IFN) signaling in a breast tumor model (MMTV-PyMT) using 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a ligand of the STimulator of Interferon Genes, STING. The 2 main events rapidly triggered by DMXAA in transplanted PyMT tumors are 1) the disruption of the tumor vasculature, followed by hypoxia and cell death; 2) the release of chemokines.