“Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer” by Katey S S Enfield et al
Cancer Discov (2024)
Abstract:
Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis.
Why this matters:
This study characterized the composition and spatial organization of the tumor microenvironment (TME) in early-stage, treatment-naïve NSCLC, and its potential link to neoantigen burden and clinical outcome. The study defines four distinct TME classes and reports on the association between high neutrophil infiltration and poor patient outcome.
“The aged tumor microenvironment limits T cell control of cancer” by Alex C Y Chen et al
Nat Immunol (2024)
Abstract:
The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
Why this matters:
This study evaluated the mechanisms driving age-associated CD8+ T cell dysfunction and identified a new subset of dysfunctional CD8+ T cells specifically associated with an aged tumor microenvironment, which are distinct from canonical exhausted CD8+ T cells, in mouse and human tumors. It shows that myeloid-targeted immunotherapies, such as CD40 agonism, can rescue age-associated defects in CD8+ T cell immunity leading to improved tumor control.
“Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment” by Kevin M Tharp et al
Nat Cancer (2024)
Abstract:
Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.
Why this matters:
This study demonstrates that a stiff fibrotic stroma drives a collagen biosynthesis program in tumor-associated macrophages (TAMs) in a TGF-β dependent manner. These collagen-synthesizing macrophages consume arginine in the tumor microenvironment and secrete ornithine which, in turn, compromises CD8+ T cell function.
“Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers” by Jan Dr Beck et al
Cancer Cell (2024)
Abstract:
Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying β2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8+ T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.
Why this matters:
Utilizing 2-microglobulin deficient mouse tumor models, this study demonstrates that MHC class I loss not only renders cancer cells resistant to CD8+ T cell recognition and killing, but also leads to an immune desert tumor microenvironment. Treatment with mRNA encoded interleukin-2 (IL-2) combined with a tumor-targeting monoclonal antibody is shown to overcome therapeutic resistance by allowing the reprogramming of tumor-resident macrophages to the M1 phenotype capable of direct tumor cell k