At present, less than 30% of researchers worldwide are women. Long-standing biases and gender stereotypes are discouraging girls and women away from science-related fields, and STEM research in particular. Science and gender equality are, however, essential to ensure sustainable development as highlighted by UNESCO. In order to change traditional mindsets, gender equality must be promoted, stereotypes defeated, and girls and women should be encouraged to pursue STEM careers. Therefore, Frontiers in Immunology is proud to offer this platform to promote the work of women scientists, across all fields of Cancer Immunity and Immunotherapy.

Head and neck cancers (HNCs) and brain tumors continue to be fatal diseases in most countries of the world. In the past decade, cancer immunotherapy has emerged as a promising therapeutic strategy and achieved unprecedented bench-to-bedside clinical success in the field of oncology. Different from traditional surgery, chemotherapy, and radiotherapy, the current cancer immunotherapy aims to recover or enhance the immune system of a patient, to recognize and eliminate cancerous cells from the primary tumor and metastases. Numerous immunotherapy strategies, in particular immune checkpoint inhibitors, adoptive cellular therapies, and cancer vaccines, are under pre-clinical investigations or in ongoing clinical trials in a range of cancer types. Among them, novel drugs have continued to be approved by the FDA, which has revolutionized the current cancer treatment by prolonging the survival time of the patients, especially in advanced unresectable tumors. However, not all patients achieve complete responses to immunotherapy due to de novo or acquired resistance. Also, immunotherapy-related adverse events are common, although it has a better safety profile than the traditional treatments. It has limited the application and efficacy of cancer immunotherapy in tumors, including the HNCs and brain tumors, and highlights the need for new strategies.

Hepatic-biliary-pancreatic cancers, mainly including hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, are highly aggressive malignancies with few treatment options and poor prognoses. Effects of the traditional systemic treatments such as chemotherapy and radiotherapy, are quite limited to hepatic-biliary-pancreatic cancers. For the patients who suffer from hepatic-biliary-pancreatic cancer and lose the opportunity of radical surgery, few targeted drugs are available. Even for the drugs in clinical trial, potential drug targets and prognostic biomarkers for hepatic-biliary-pancreatic cancer are less studied compared to other common cancers such as lung cancer. Prognostic biomarker study is the initiation to explore new drug targets and revelation of the underlying mechanisms of tumor progression. Immunotherapy, especially PD1 or PD-L1 antagonists, has exhibited potent treatment effects on cancers. To date, many PD1 drugs are available for cancer treatment, and more than one hundred PD1 drugs are in clinical trial. However, how to screen out the sensitive patients and predict the efficacy of immunotherapy are still unsolved problems. Moreover, the predictive biomarkers and treatment guidelines of immunotherapy for hepatobiliary tumors are barely investigated.

Gastrointestinal (GI) cancers, including gastric cancer, colon cancer, liver cancer, esophageal cancer, and pancreatic cancer, seriously threaten the health of human beings worldwide with a high rate of morbidity and mortality. The clinical successes achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 have opened a new cancer therapy era and brought new hope to cancer patients. However, the overall response rate (ORR) of ICI monotherapy in the non-selective population is only about 20%, in which some patients subsequently develop immunotherapy resistance. Moreover, the remaining 70-80% of patients displayed primary resistance to ICIs, and a few patients even experienced hyper progression disease (HPD). Although PD-L1 expression, mismatch repair deficient (MMRd), high tumor mutational burden (TMB-H) , high homologous recombination deficiency (HRD), and tumor infiltrated immune cells (TILs) are known as effective biomarkers for immunotherapy, growing studies have reported that ICIs could not improve the OS of all patients with PD-L1 expression higher than 50%, and the ORR of MSI-H patients was only about 60%, whereas some patients with low PD-L1 expression or MSS could still benefit from immunotherapy, indicating the complexity of ICI resistance. Therefore, it is of great importance and significance to explore the prediction biomarkers for primary or acquired immunotherapy resistance and elucidate their underlying molecular mechanisms and develop reversal strategies. Due to the multiple steps of the cancer immune cycle and complex immune microenvironment, any disorders of immune cell infiltration or T cell activation, such as lack of antigens and/or their presentation, lack of response to antigen presentation, and T cell priming, could contribute to ICI resistance. The combination with anti-angiogenesis therapy, radiotherapy, chemotherapy, and other ICIs has improved the efficacy of ICI therapy to some extent in the clinic. Although numerous studies related to ICI resistance were reported in GI cancers, due to the strong spatial/temporal heterogeneity and the complex immune microenvironment in different kinds of GI cancers and different individuals, many questions about ICI resistance and reversal strategies remain unsolved. The aim of this Research Topic is to provide a forum to exhibit the latest research achievement related to the exploration of biomarkers for immunotherapy resistance including HPD and the underlying molecular mechanisms, as well as the development of reversal strategies in GI cancers. We hope this Research Topic will lead to a better understanding of precision cancer immunotherapy and provide useful clues for clinical application to benefit more GI cancer patients with immunotherapy.

This Research Topic is part of the “Methods in Immunology” series. Please submit your article to the Research Topic that best suits the focus of your research. Introduction and general guidelines: This series aims to highlight the latest experimental techniques and methods used to investigate fundamental questions in Immunology research, with a focus on Cancer Immunity and Immunotherapy.

Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, has revolutionized the paradigm in cancer treatment. However, the clinical outcome of immunotherapy varies considerably among patients and only a minority of patients achieve long-term clinical benefits. This is largely attributed to the fact that existing cancer immunotherapies, which concentrate on several classical targets (CTAL-4, PD-1/PD-L1, etc.) and limited types of immune cell populations (T cells), are insufficient to cope with the complexity of highly heterogeneous tumor microenvironment (TME). This calls for more efforts to not only expand our toolbox for manipulating anticancer immunity but also diversify our combinational strategies. To this end, it is urgent to deeper our understanding of cancer immunotherapy by using both experimental and computational methodologies from multi-scale perspectives: 1) novel targets from either tumor cells or non-tumor cells within TME (e.g., tumor intrinsic resistance drivers, new immune checkpoints, neoantigens), 2) in-depth characterization of more immune cell populations (e.g., macrophages, Tregs, B cells) and their interactions and dynamics within TME, 3) landscape of actionable targets in patient populations for combination design. These efforts will open the avenue of rational design of combinational immunotherapies, allowing researchers and clinicians to design novel targeting therapeutics or to optimally orchestrate combinatory strategies aiming to surmount resistance mechanisms and improve clinical outcomes.