The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy.

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8+ or NK cells, there are clear evidences that CD4+ T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4+ T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa. These data might be important designing better interventions that unleash the full potential of immune response against cancer.

Lee J ，Lozano-Ruiz B ，Yang FM ，Fan DD ，Shen L ，González-Navajas JM ... -  《Frontiers in Immunology》

Differentiation and Regulation of T(H) Cells: A Balancing Act for Cancer Immunotherapy.

Current success of immunotherapy in cancer has drawn attention to the subsets of TH cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic TH subsets in the tumor milieu further contributes to the complexity of regulation of TH cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory TH9 and Tfh cells, immunosuppressive Treg cells, and the duality of TH17 function contribute to tip the balance of anti- vs pro-tumorigenic TH responses in the tumor. We highlight the developing knowledge of CD4+ TH1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4+ TH1 immunity, and how opposing action of TH cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4+ TH cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic TH subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.

Basu A ，Ramamoorthi G ，Albert G ，Gallen C ，Beyer A ，Snyder C ，Koski G ，Disis ML ，Czerniecki BJ ，Kodumudi K ... -  《Frontiers in Immunology》

Editorial: CD4(+) T Cells in Cancer Immunotherapies.

González-Navajas JM ，Elkord E ，Lee J 《Frontiers in Immunology》

Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer.

The tumor microenvironment includes a complex network of immune T-cell subpopulations. In this study, we systematically analyzed the balance between cytotoxic T cells and different subsets of helper T cells in human colorectal cancers and we correlated their impact on disease-free survival. A panel of immune related genes were analyzed in 125 frozen colorectal tumor specimens. Infiltrating cytotoxic T cells, Treg, Th1, and Th17 cells were also quantified in the center and the invasive margin of the tumors. By hierarchical clustering of a correlation matrix we identified functional clusters of genes associated with Th17 (RORC, IL17A), Th2 (IL4, IL5, IL13), Th1 (Tbet, IRF1, IL12Rb2, STAT4), and cytotoxicity (GNLY, GZMB, PRF1). Patients with high expression of the Th17 cluster had a poor prognosis, whereas patients with high expression of the Th1 cluster had prolonged disease-free survival. In contrast, none of the Th2 clusters were predictive of prognosis. Combined analysis of cytotoxic/Th1 and Th17 clusters improved the ability to discriminate relapse. In situ analysis of the density of IL17+ cells and CD8+ cells in tumor tissues confirmed the results. Our findings argue that functional Th1 and Th17 clusters yield opposite effects on patient survival in colorectal cancer, and they provide complementary information that may improve prognosis.

Tosolini M ，Kirilovsky A ，Mlecnik B ，Fredriksen T ，Mauger S ，Bindea G ，Berger A ，Bruneval P ，Fridman WH ，Pagès F ，Galon J ... -  《-》

PSGL-1 Immune Checkpoint Inhibition for CD4(+) T Cell Cancer Immunotherapy.

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4+ T cells in numerous disease settings including cancer. PSGL-1 is highly expressed on T cells and can engage numerous ligands that impact signaling pathways, which may modulate CD4+ T cell differentiation and function. PSGL-1 engagement in the tumor microenvironment may promote CD4+ T cell exhaustion pathways that favor tumor growth. Here we highlight that blocking the PSGL-1 pathway on CD4+ T cells may represent a new cancer therapy approach to eradicate tumors.

DeRogatis JM ，Viramontes KM ，Neubert EN ，Tinoco R ... -  《Frontiers in Immunology》