The Immune Contexture Associates with the Genomic Landscape in Lung Adenomatous Premalignancy

Abstract

Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8 þ and CD4 þ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy. Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy. See related commentary by Merrick, p. 4811

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

“…Estrogen targeting agents may therefore be especially effective in those patients with underlying inflammatory conditions such as chronic obstructive pulmonary disease or emphysema, who already show heightened immunosuppression. Since immune responses are also observed in very early lung premalignancies, hormonal modulation may play a role in the prevention setting as well (178,179). As an increased focus is being placed on the interaction between tumor cells and the cells within the TME, the role of estrogen within this context provides a unique perspective that can fit within this complex and constantly changing paradigm.…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…This was accompanied by inhibition of IFNG and TGFB1 signaling, reduction in inflammatory responses, and increased expression of CCL2/CCR2, SPP1, and CD27 (191). In another cohort, somatic mutations in AAHs that progressed and persisted in LUADs were not only shown to be highly heterogeneous between PMLs of different patients, but they also produced putative progressive neoantigens that were expressed in the earliest pulmonary PMLs and persisted throughout tumor progression (179). Further, the PML neoantigen load correlated with the extent of CD8+ and CD4+ T cell infiltration and upregulation of PD-L1 (179).…”

“…Yet, some tumors with high mutational load are surprisingly unresponsive to ICB treatment, and a deeper investigation revealed additional factors that influence neoantigen presentation and response to ICB. For instance, it has been proposed that the quality of neoantigens provide a better reflection of tumor immune landscape compared to the quantity of neoantigens and this has been possible thanks to neoantigen prediction algorithms and advanced in silico models (176)(177)(178)(179). For instance, long-term survival of patients with pancreatic cancer correlated with neoantigen "foreignness, " an attribute of their homology to antigens derived from infectious diseases, rather than the actual number of neoantigens, a timely observation given the emerging roles of tumor microbiomes (further discussed below) (177).…”

“…Further investigation suggested that HLA LOH is an immune escape mechanism that is subject to strong selection pressures from the microenvironment thereby influencing tumor evolution. Additionally, the affinity with which HLAs bind to their respective neoantigens has been a subject of interest in cancer immunogenomics, and an area that is expanding in silico immunogenomic tools, such as neoantigen prediction software which are being used to predict both HLA binding affinities for each tumor-specific antigen (179,187).…”

“…It has become evident that intact and balanced microbiota, on its own merit, has a positive impact on the health and physiology of the host by influencing a variety of biological functions ranging from behavior, to obesity and cancer (217). Indeed, the microbiome has been dubbed as a "key orchestrator of cancer therapy, " modulating chemotherapy, radiotherapy and immunotherapy ↓ Anti-tumor Th1 (IL12A, GZMB) ↑ Pro-tumorigenic Th2 ↑ Pro-inflammatory cytokines (IL-6, TNF-α) in AAH (190,191) ↓ Anti-tumor Th1 (IL12A) ↑ Pro-tumorigenic Th2 ↑ Immune suppressive mechanisms (IL6, IL10) (191,192) ↑ Immune checkpoints (PD-L2, LAG-3) in Lynch syndrome (193) ↑ Immune checkpoints (CTLA-4, CCR2) (191) ↑ Immune checkpoints (PD-1, CTLA−4, VISTA, LAG−3, TIM-3) (191) ↑ CD4+ and CD8+ TILs (194) ↑ Exhausted CD8+ TILs reactive to neoantigens (195) ↓ Cell-mediated immune response (195) Uncontrolled TLR signaling (196,197) ↑ TLR and inflammatory mediators (NF-κB) ↑ downstream chemokines (IL-6, IL−17) (198) ↓ TLR, ↓ Effector cytokine production (IFN-γ, TNF-α) (199) Progressive infiltration of innate immunosuppressive cells and M2 macrophages and T regs in OPLs (188,200) Immature macrophage-lineage cell infiltration (201) Massive tumor immune cell infiltration (201) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (202) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) Common tumor antigens between cancers and PMLs (203) ↑ Neoantigen expression in due to infiltration of CD4+ and CD8+ T cell as well as ↑ PD-1 (179) ↑ Immunogenic neoantigen load activating anti-tumor T cell response (195) Humoral cell-mediated immune response activated against TAA in gastric premalignant lesions (204) Activation of cell-mediated immune response and recognition of neoepitopes (179) Activation of cell-mediated immune response and recognition of neoepitopes (179) Very few chromosomal mutations (TP53 in Barret's esophagus) …”