Comment in Cancer Cell. 2022 Jun 13;40(6):595-597.

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Comment in Cancer Cell. 2022 Jun 13;40(6):597-599.

T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages (TAMs) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAMs reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+ T cells engage in unique, long-lasting, antigen-specific synaptic interactions that fail to activate T cells but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.

Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.

Comment on N Engl J Med. 2022 May 26;386(21):1973-1985.

Comment in Cancer Cell. 2022 Jun 13;40(6):592-594.

The success of chimeric antigen receptor (CAR) T cell therapy in solid tumors, unlike in hematologic malignancies, is limited by inadequate tumor infiltration and T cell dysfunction and exhaustion. Regional delivery of CAR T cells in patients with solid tumors is safe and feasible; promotes infiltration, proliferation, and trafficking; and ignites functionally persisting systemic immunity.

Comment on Cell. 2022 Apr 14;185(8):1356-1372.e26.

Comment on Cancer Cell. 2022 Jun 13;40(6):609-623.e6.

Author information: (1)Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3)Department of Biostatistics, Vanderbilt University, Nashville, TN, USA. (4)LUNGevity Foundation, Bethesda, MD, USA. (5)Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6)GO2 Foundation for Lung Cancer, Washington, DC, USA. (7)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8)Hamon Center for Therapeutic Oncology Research, Departments of Internal Medicine and Pharmacology UT Southwestern Medical Center, Dallas, TX, USA. (9)Diagnostic, Molecular and Interventional Radiology, Mount Sinai Health System, New York, NY, USA. (10)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11)Department of Internal Medicine, University of Colorado Cancer Center, Denver, CO, USA. (12)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13)Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14)Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: fred.hirsch@mssm.edu.

Animal models have evolved to be a key component of translational research of cancer, and they are now extensively used to test drug candidates, predict drug responses, and essentially drive discovery of cancer biology. However, the model-centric approach has not yielded the expected abundance of treatment advances. We propose that the focus of translational research needs to shift from animal models to human patients, and the goal should be to understand why tumor responses and outcomes are so variable between patients and how it can be predicted at the individual level and thus to generate hypotheses that are more relevant to people than to atypically sensitive animal models.

The CheckMate 649 trial, recently published in Nature, established chemotherapy plus nivolumab as a standard in advanced, treatment-naive gastroesophageal adenocarcinoma, with best results seen in patients with high PD-L1 expression and microsatellite unstable tumors. In contrast, nivolumab plus ipilimumab, compared with chemotherapy, showed early progression and no overall survival benefit.

Comment on Cancer Cell. 2022 Jun 13;40(6):656-673.e7.

Comment on Cancer Cell. 2022 Jun 13;40(6):674-693.e7.