Background: While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. Methods: Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances T_H9 cell antitumor activity against mouse melanoma upon adoptive transfer. Results: We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T_H1 and T_H9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of T_H1 cell differentiation. However, STING activation favors T_H9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on T_H1 and T_H9-derived cytokines, and STING activation enhances the antitumor activity of T_H9 cells upon adoptive transfer. Conclusion: Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

The catabolic process of autophagy plays important functions in inflammatory and immune responses by modulating innate immunity and adaptive immunity. Over the last decade, a cell-intrinsic role for autophagy in modulating CD4 T cell functions and differentiation was revealed. After the initial observation of autophagosomes in effector CD4 T cells, further work has shown that not only autophagy levels are modulated in CD4 T cells in response to environmental signals but also that autophagy critically affects the biology of these cells. Mouse models of autophagy deletion in CD4 T cells have indeed shown that autophagy is essential for CD4 T cell survival and homeostasis in peripheral lymphoid organs. Furthermore, autophagy is required for CD4 T cell proliferation and cytokine production in response to T cell receptor activation. Recent developments have uncovered that autophagy controls CD4 T cell differentiation and functions. While autophagy is required for the maintenance of immunosuppressive functions of regulatory T cells, it restrains the differentiation of T_H9 effector cells, thus limiting their antitumor and pro-inflammatory properties. We will here discuss these findings that collectively suggest that therapeutic strategies targeting autophagy could be exploited for the treatment of cancer and inflammatory diseases.

: Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

The increasing incidence of anal canal carcinomas requires better knowledge on anal human papillomavirus (HPV) infection. We aimed to assess anal canal HPV infection prevalence and risk factors among patients seen at a gastroenterology department in France. We analyzed anal tissue samples collected from 469 consecutive patients (median age 54 years, 52% women), including 112 who received immunosuppressant therapies and 101 with inflammatory bowel disease (70 with Crohn's disease), who underwent colonoscopy examinations from April 1, 2012 to April 30, 2015. HPV was detected and genotyped using the INNO-LiPA assay, and we collected medical and demographic data from all subjects. Risk factors for any HPV, high-risk HPV (HR-HPV) and HPV16 infection were assessed by bivariate and multivariate analysis. The primary outcomes association of HR-HPV or HPV16 with medical and demographic features. We detected HPV DNA in anal tissues from 34% of the subjects and HR-HPV in 18%. HPV16 was the most prevalent genotype (detected in 7%), followed by HPV51, HPV52, and HPV39. HR-HPV was detected in a significantly higher proportion of samples from women (23.1%) than men (12.8%) (P = .0035); HR-HPV and HPV16 were detected in a significantly higher proportion of patients with Crohn's disease (30.0%) than without (18.1%) (P = .005). Female sex, history of sexually transmitted disease, lifetime and past year-number of sexual partners, active smoking, and immunosuppressive therapies were independent risk factors for anal HR-HPV infection in multivariate analysis. One third of patients who underwent colonoscopy at a gastroenterology department were found to have anal canal HPV infection. We detected HR-HPV infection in almost 20% of patients and in a significantly higher proportion of patients with Crohn's disease than without. Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening.

Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (T_reg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of T_regs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of T_reg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.