Series on Cancer Immunotherapy

The advent of immunotherapy has revolutionized the cancer field, but it is not without its challenges. In this issue, we launch our Series on Cancer Immunotherapy presenting commissioned Reviews and opinion pieces on the latest advances and efforts to expand the palette of immunotherapies and their clinical translation.

Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic.

Melero and colleagues discuss the current landscape of immunotherapy combinations, ongoing clinical studies and the translational implications for efficacy and safety across tumor types.

Tumor mutational burden (TMB) has received significant attention within ongoing pursuits of biomarkers of response to immune checkpoint inhibitors, and notably received FDA approval as a companion diagnostic biomarker for pembrolizumab. Here, four experts discuss the utility, challenges, and open questions surrounding TMB in the context of cancer immunotherapy.

Wells and colleagues discuss emerging insights into bystander T cells, including analytical methods, the role of bystander T cell subtypes in tumor immunology and the potential ways that these cells can be leveraged to improve cancer immunotherapy.

Hwang and colleagues discuss recent advances and current challenges in developing immunotherapies for pediatric brain cancer, as well as the clinical implications of ongoing and completed studies.

Melenhorst and colleagues review the current status of chimeric antigen receptor T cell therapies, focusing on the rapid progress achieved in this area of immunotherapy, but also the challenges to be overcome.

Cancer vaccines can elicit tumor-specific T cells, but sustaining their function via immune checkpoint therapy (ICT) may be required for robust anti-tumor immunity. A new study reveals that neoantigen cancer vaccines synergize with anti-PD-L1 ICT in a preclinical model and provides mechanistic insights into this synergy.

Severe side effects limit the therapeutic potential of checkpoint control and immunomodulatory antibodies in immunotherapy of cancer. A new study demonstrates that bispecific antibodies directing the immunostimulatory activity of CD40-specific antibodies on dendritic cell subsets may allow a greater therapeutic window of opportunity.

Cellular communication in the tumor microenvironment is crucial for T cell activation; however, the molecular features of the T cell–antigen-presenting cell interaction are still poorly understood. A new study utilizes RNA sequencing of physically interacting cells to reveal that PD-1⁺CXCL13⁺ helper T cells in tumors, primed by dendritic cells, are important for the response to immunotherapy.

Two of the first patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells have been cancer free for a decade. A new study uses single-cell sequencing technologies to provide a window into the evolution of their CAR T cells over the course of the ten-year remission period.

Despite the profound clinical success of immune-checkpoint inhibitors, their effectiveness is limited by intrinsic and acquired resistance. Bullman, Zitvogel and colleagues provide their views on two clinical trials modulating the microbiome of immunotherapy-resistant patients with melanoma via transplantation of fecal microbiota from patients who responded to immunotherapy.

Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.

CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.

Combining radiation and immune checkpoint blockade is a promising treatment strategy, yet the mechanisms and optimal dosing strategies are not well known. A new study finds that a specific radiation dose can activate secretory club cells to promote the anti-tumor effects of radiotherapy combined with immunotherapy in NSCLC.

Prostate cancer is largely unresponsive to immunotherapy. A new study finds elevated expression of the chemokine IL-8, or its mouse homolog Cxcl15, in prostate cancer after castration, which leads to the recruitment of immunosuppressive myeloid cells. Blocking tumor infiltration with these cells could improve the response to immune-checkpoint inhibition and androgen-deprivation therapy.

Two recent studies demonstrate how autophagy, in both tumor cells and host tissues, regulates anti-tumor T cell responses. These works add to accumulating evidence that inhibitors of autophagy could be used in combination with immunotherapy in certain cancer types.

Achieving depletion of regulatory T cells while sparing tumor-specific effector T cells has long remained an elusive goal of immunotherapy. A new study describing the development of an antibody to the cytokine receptor CD25 optimized to ensure depletion of regulatory T cells without blocking binding of the cytokine IL-2 will reinvigorate interest in this therapeutic avenue.

The response to immunotherapy has been linked to human leukocyte antigen (HLA) genotype in certain cancers. A new study examining the interaction between cancer type–specific mutational exposures and the B44 and B27 HLA supertypes finds that patients with mutant peptides complementary to these supertypes receive the most benefit from immune-checkpoint blockade.

Immunostimulatory agents such as Toll-like receptor (TLR) agonists have shown promising antitumor efficacy but are associated with therapy-related toxicities when delivered systemically. Immune-stimulating antibody conjugates are now shown to deliver TLR agonists with potent preclinical antitumor activities.

Fuchs and colleagues delineate a mechanism by which PARP11-mediated IFNAR1 loss sustains an immunosuppressive tumor microenvironment and show that PARP11 inactivation can enhance chimeric antigen receptor T efficacy in preclinical solid tumor models.

Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.

Li and colleagues use single-cell techniques to identify features of T cells in the tumor and draining lymph nodes involved in the efficacy of immune checkpoint blockade combined with a neoantigen vaccine in preclinical models.

Hua and colleagues develop CAR T cells targeting CDH17 and show that they are effective at suppressing tumor growth in mouse and human models of neuroendocrine and gastrointestinal solid tumors, without damaging healthy tissues in preclinical models.

Celià-Terrassa and colleagues identify LCOR-low cancer stem cells driving tumor immunity and propose LCOR induction with mRNA therapy as an enhancer of immunotherapy response.

Alvarez and colleagues develop a bispecific anti-PD-1–GITR-L agonist that activates T cells via a mechanism distinct from those found with individual PD-1 and GITR-L agonists and demonstrate its antitumor activity in mice and nonhuman primates.

Amit and colleagues report that the specific interaction of a CD4⁺PD-1⁺CXCL13⁺ T-cell subset with antigen-presenting cells reprograms the tumor microenvironment and response to immune checkpoint inhibitors in non-small cell lung cancer.

Dahan and colleagues develop bispecific antibodies to overcome toxicities associated with CD40 agonists by preferentially targeting CD40 activation to dendritic cells, demonstrating effective antitumor immunity in multiple murine solid tumor models.

Saur and colleagues perform a high-throughput combinatorial drug screen and identify a synergistic combination between nintedanib and trametinib that sensitizes mesenchymal PDAC to immune checkpoint blockade.

Zhang and colleagues analyzed patients with lung cancer treated with anti-PD-1 with single-cell methods, finding the presence of precursor exhausted T cells in responders that accumulated through local expansion and clonal revival from peripheral T cells.

Kang and colleagues demonstrate that pharmacological targeting of the MTDH1–SND1 axis prevents immune evasion during metastatic progression and provides a synergistic combination strategy with immune-checkpoint blockade to treat metastasis.

In two cohorts of patients with glioblastoma who received anti-PD-1, Sonabend and colleagues show that ERK1/2 phosphorylation, detected by immunohistochemistry, provides a biomarker for MAPK/ERK pathway activity and better survival on this therapy.

Ting and colleagues report the safety and efficacy of combined radiation and immunotherapy in a phase II trial on patients with MSS colorectal or pancreatic cancer and observe that disease control correlates with higher repetitive RNA transcription.

Using in vivo models and human cancer datasets, Yang and colleagues identify a role for the epigenetic regulator Rnf2 in repressing the antitumor immune responses of natural killer and CD4⁺ T cells.

Jacks and colleagues demonstrate the effects of neoantigen expression level on T-cell priming and immune surveillance during tumor development and progression and explore implications for immunotherapies, using in vivo models of colorectal cancer.

Dotti and colleagues present a CAR design featuring trans-acting CD28 and 4-1BB co-stimulation and shared CD3ζ-chain, which improved CAR-T cell metabolic and antitumor functions and avoided tumor escape through simultaneous targeting of two antigens.

Mittal and colleagues investigate the mechanisms underlying the therapeutic effects of radiation therapy in combination with checkpoint blockade, finding a role for activated lung-resident secretory club cells in modulating antitumor immune responses.

Italiano and colleagues demonstrate the utility of mature tertiary lymphoid structures to predict response to immunotherapy, with pathologic analysis in three independent patient cohorts spanning multiple tumor types.

Chinnaiyan and colleagues perform a high-throughput compound screen and identify PIKfyve inhibition as a therapeutic strategy to enhance immune checkpoint blockade responses in advanced prostate cancer.

Yarchoan and colleagues present a single-arm phase 1 clinical trial of cabozantinib with immune checkpoint inhibition for patients with hepatocellular carcinoma. Using high-dimensional spatial analysis, they identify immune features enriched in responders.

Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.

Manczinger and colleagues define ‘promiscuity’ as a feature of HLA-I alleles representing peptide repertoire breadth; promiscuous alleles may promote a more tolerant tumor microenvironment and negatively impact tumor immune surveillance.