Co-mutations in Tumor Immune Microenvironment and Immunotherapy
The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression and response to therapy. It comprises various cell types, including fibroblasts, macrophages, endothelial cells, and immune cells. The heterogeneity of the tumor immune microenvironment (TIME) significantly influences the response of different patients to immunotherapy. Among the most promising advances in cancer treatment is the use of immune checkpoint inhibitors (ICIs), which target pathways such as programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the response rates to ICIs remain relatively low, and the predictive biomarkers for treatment efficacy are often inconsistent. This highlights the urgent need for novel and reliable biomarkers to monitor tumor-specific immune responses, minimize immune-related adverse events, and improve clinical outcomes.
Genomic alterations are key drivers of tumor biology, microenvironment, and treatment susceptibility, particularly in lung cancer. Co-occurring genomic alterations, or co-mutations, have emerged as core determinants of molecular and clinical heterogeneity in oncogene-driven lung cancer subgroups. This article focuses on the association of co-mutations with TIME and immunotherapy, with a particular emphasis on lung cancer.
Co-mutations Within KRAS-mutations Associated with TIME and Immunotherapy
KRAS mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC), accounting for 25% to 30% of lung adenocarcinoma (LUAC). Skoulidis et al. identified three distinct subgroups of KRAS-mutant LUAC based on co-mutations: the KL subgroup, characterized by co-mutations in KRAS and serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1); the KP subgroup, featuring co-mutations in KRAS and tumor protein p53 (TP53); and the KC subgroup, marked by inactivation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and suppressed neurokinin A (NK2) homeobox 1/thyroid transcription factor 1 expression. Additionally, KRAS mutations co-occur with other gene mutations, such as kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (KEAP1)/nuclear factor erythroid 2-like 2 (NRF2; also known as NFE2L2), RNA binding motif protein 10, protein tyrosine phosphatase receptor type D, and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4). These co-mutations contribute to the clinical heterogeneity of KRAS-mutant NSCLC and offer potential predictive biomarkers for survival and therapy.
KL: KRAS and STK11/LKB1 Co-mutations
The KL subgroup, characterized by co-mutations in KRAS and STK11/LKB1, is associated with a “cold” TIME. Studies have shown that LKB1 loss is more frequent in tumors with KRAS transversion mutations, and patients with KL co-mutations have a higher risk of brain metastasis. STK11/LKB1 inactivation is linked to reduced densities of infiltrating CD3+, CD4+, and CD8+ T lymphocytes, lower PD-L1 expression in tumor cells, decreased stimulator of interferon genes (STING) levels, increased neutrophil recruitment, T cell dysfunction, and elevated proinflammatory cytokine production. KL tumors exhibit suppressed expressions of immune markers, such as PD-L1 and CD274 messenger RNA (mRNA) levels. Koyama et al. demonstrated that T-cell numbers and function could be improved by depleting neutrophils or blocking the cytokine feedback loop using a neutralizing anti-IL6 antibody in Kras/Lkb1-mutant mice. Furthermore, STK11/LKB1 alterations negatively correlate with PD-L1 expression in tumor mutational burden (TMB) intermediate/high LUAC. STK11/LKB1 is identified as the most prevalent genomic driver of primary resistance to PD-1/PD-L1 blockade in KRAS-mutant LUAC, providing a theoretical basis for predicting clinical efficacy of PD-1 axis inhibitors in this subgroup.
KP: KRAS and TP53 Co-mutations
The KP subgroup, characterized by co-mutations in KRAS and TP53, is associated with an immunologically “hot” TIME. TP53, the most frequently mutated gene in cancer, is altered in approximately half of all human tumors. Studies have shown that PD-L1 positivity in tumor cells is significantly correlated with p53 aberrant expression, PD-L1 positivity in tumor-infiltrating immune cells, and higher disease stage in LUAC patients. KP LUACs exhibit elevated interferon-gamma (IFN-g), PD-L1, PD-1, CTLA-4, and increased densities of infiltrating CD3+, CD8+, and CD45RO+ T lymphocytes. Compared to the KL subgroup, KP tumors show higher expressions of PD-L1 and CD274. Skoulidis et al. confirmed the enrichment of somatic mutations, inflammation, activated anti-tumor immunity, and immune tolerance/escape in the KP subgroup. Patients with KP co-mutations undergoing pembrolizumab treatment have shown prolonged progression-free survival (PFS) and durable clinical benefit, suggesting that ICIs may be effective therapeutic strategies for KP tumors. However, more clinical studies, particularly multicenter prospective randomized controlled trials, are needed to validate these findings.
KC: KRAS Mutation and CDKN2A/B Inactivation
The KC subgroup, characterized by KRAS mutations and CDKN2A/B inactivation, demonstrates a mixed immune system engagement with moderate CD274 mRNA expression compared to KP or KL tumors. In metastatic KRAS-mutant NSCLC, somatic genomic alterations in CDKN2A and CDKN2B account for approximately 20% and 12%, respectively. CDKN2A/B loss accelerates mutant Kras-driven lung tumorigenesis and metastasis in genetically engineered mouse models and decreases overall survival (OS) in KRAS-mutant LUAC patients. Studies have shown that the deletion region of 9p21.3 (CDKN2A/B) is among the most frequently identified regions in gliomas with high immune cytolytic activity, suggesting a complex and strong immune response system. These findings indicate that KC tumors may help predict clinical efficacy from ICIs, but more clinical data are needed to validate these correlations.
KRAS, STK11/LKB1, and KEAP1 Co-mutations
Co-mutations of KRAS and KEAP1 are associated with decreased OS from the start of ICIs in NSCLC patients. KL tumors have high rates of KEAP1 mutational inactivation, which, when co-occurring with additional KEAP1 mutations, exhibit low intra-tumoral density of infiltrating T and B lymphocytes, decreased PD-L1 expression in tumor cells, and reduced STING levels. KEAP1 encodes an adaptor protein that negatively regulates NRF2-mediated transcription and further reduces STING expression via post-transcriptional regulation.
Other Co-occurring Genomic Events Associated with TIME and Immunotherapy
ALK Receptor Tyrosine Kinase (ALK) and TP53 Co-mutations
ALK and TP53 co-mutations predict an unfavorable outcome of systemic therapy in NSCLC. PD-L1 positivity is significantly associated with TP53 mutation status in ALK-positive patients, suggesting that ALK and TP53 co-mutations may positively influence the clinical efficacy of ICIs. However, these results are based on a limited clinical sample, and larger studies are needed to confirm these associations.
Epidermal Growth Factor Receptor (EGFR) and Mitogen-Activated Protein Kinase (MAPK) Co-mutations
EGFR and MAPK co-mutations are associated with higher TMB and PD-L1 levels compared to other EGFR co-mutant patterns and EGFR single-mutant patients. This subgroup exhibits a favorable TIME, characterized by upregulated T cells, B cells, and Fc gamma receptor-mediated phagocytosis. L858R mutations are more frequently found with higher TMB compared to exon 19 deletions in EGFR co-mutations. Although most ICI studies exclude patients with EGFR mutations, LUAC with EGFR and MAPK co-mutations may benefit from ICI treatment. Further clinical studies are needed to confirm these findings and underlying mechanisms.
KEAP1-driven Co-mutations
LUAC patients with co-mutations in KEAP1 and polybromo 1 (PBRM1), SMARCA4, or STK11 exhibit higher TMB and a distinct immunogenomic landscape of T-cell receptor repertoire, T helper cell signatures, core immune signatures, and immunomodulatory genes compared to wild-type groups. However, KEAP1-driven co-mutations are more likely to be unresponsive to immunotherapy and are associated with inferior survival outcomes. These co-mutations are linked to immunologically “hot” tumors but are resistant to immunotherapy, possibly due to the complex TIME and tumor heterogeneity.
Impact of Immunoediting on Co-mutations
Immunoediting, the process by which the immune system shapes the mutational landscape of tumors, plays a critical role in the development of co-mutations. Antigenic oncogenic mutations can be eliminated by immunosurveillance during the early stages of tumor development, as demonstrated in mouse models. Immunodeficient mice are more susceptible to cancers with immunogenic tumor cells compared to immunocompetent mice. Lymphocytes and IFN-g restrict tumor immunogenicity and spontaneous tumor formation. Reduced tumor antigen expression or presentation on major histocompatibility complex class I (MHC-I) allows primary sarcomas to escape T lymphocyte attack. A “cold” TIME likely relaxes immune selection, resulting in a more diverse spectrum of co-mutations. Recent studies have shown that MHC-I genotype-restricted immunoediting shapes the mutational landscape during tumor formation, and an individual’s MHC-I genotype-based score can predict oncogenic mutations. This immunoediting process may influence the patterns of co-mutations, which need further validation.
Conclusions
This article summarizes the role of co-mutations in TIME and immunotherapy. The subgroups of KRAS mutations, including ALK and TP53 co-mutations, EGFR and MAPK co-mutations, and KEAP1-driven co-mutations, exhibit molecular and biological diversity, explaining the different TIME and therapeutic efficacies of immunotherapy. Immunoediting also impacts the patterns of co-mutations in lung cancer. However, these conclusions require further confirmation through multicenter and prospective clinical studies. In the era of precision medicine, co-mutations may help identify subsets of patients most likely to benefit from immunotherapy, paving the way for personalized immune-based therapies.
doi.org/10.1097/CM9.0000000000001455
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