Co-Mutation of FAT3 and LRP1B in Lung Adenocarcinoma Defines a Unique Subset Correlated With the Efficacy of Immunotherapy

Immunotherapy based on immune checkpoint inhibitors (ICIs) have demonstrated remarkable survival benefits and gained regulatory approval in non-small cell lung cancer (NSCLC) patients without an actionable driver mutation, but currently there is no well-established standard for how to screen the most suitable population for ICIs treatment. Here, we conducted a comprehensive analysis of the somatic mutation landscape of lung adenocarcinoma (LUAD) samples. After the stepwise screening of high-frequency mutated genes, two genes with prominent significance, FAT3 and LRP1B, were finally screened out. Through further analysis, we discovered that the co-mutation of FAT3 and LRP1B was associated with an earlier age of onset and occurred more frequently in Black/African American. Furthermore, co-mutation defines a unique subgroup of lung adenocarcinoma that can increase tumor mutational burden (TMB), boost cytotoxicity and tumor immunogenicity, and facilitate lymphocyte infiltration. The results of gene set enrichment analysis (GSEA) indicated that co-mutation can influence tumorigenesis through a variety of mechanisms. More strikingly, the subset of LUAD with co-mutation of FAT3 and LRP1B exhibited significantly prolonged immunotherapy progression free survival (PFS). In summary, co-mutation of FAT3 and LRP1B is a promising useful biomarker for predicting the efficacy of immunotherapy, which can improve the clinical efficiency of practicing precision medicine in lung adenocarcinoma patients.

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Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21032 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21032-e21032

Author(s):

Xuanzong Li ◽

Linlin Wang

Keyword(s):

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Rank Test ◽

Wild Type ◽

Exact Test ◽

Entire Cohort ◽

Kaplan Meier ◽

Tumor Mutational Burden ◽

The Difference ◽

Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

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PTPRD/PTPRT mutations as potential positive predictor for response of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15112 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15112-e15112

Author(s):

Jian Zeng ◽

Guoqiang Wang ◽

Zhengqing Yan ◽

Hao Zheng ◽

Jianqiang Li ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Small Cell ◽

Gene Set Enrichment Analysis ◽

Small Cell Lung ◽

Gene Set Enrichment ◽

Nsclc Patients

e15112 Background: Immune checkpoint inhibitors (ICIs) have demonstrated positive results in non-small cell lung cancer (NSCLC) patients, with durable responses and prolonged overall survival (OS). Nevertheless, the response rate to immunotherapy is still limited. It is necessary to identify clinically useful biomarkers that can distinguish patients who can respond to ICIs. PTPRD/PTPRT are the phosphatases of JAK-STAT signaling, which may be associated with response to ICIs. Here we aimed to demonstrate the association between PTPRD/PTPRT and ICIs. Methods: Genomic and survival data of NSCLC patients administrated with anti–PD-1/PD-L1 or anti–CTLA-4 antibodies (Rizvi2015; Hellmann2018; Rizvi2018 Samstein2019) were retrieved from publicly accessible data. Genomic, survival and mRNA data of 1007 patients with NSCLC was obtained from The Cancer Genome Atlas (TCGA). Association between PTPRD/PTPRT mutation and progression-free survival (PFS) and overall survival (OS) were analyzed. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: PTPRD/PTPRT mutations were significantly associated with better PFS in Rizvi2015 cohort (HR = 0.16; 95% CI, 0.02-1.17; P = 0.03), Hellmann2018 cohort (HR, 0.49; 95% CI, 0.26-0.94; P = 0.03) and Rizvi2018 cohort (HR = 0.64; 95% CI, 0.44-0.92; P = 0.01). PTPRD/PTPRT mutation was also significantly associated with better OS in Samstein2019 cohort (HR, 0.66; 95% CI, 0.45-0.97; P = 0.03). In TCGA, no association between PTPRD/PTPRT mutations and OS was observed (P = 0.91), suggesting that PTPRD/PTPRT mutations were not prognostic factor. PTPRD/PTPRT mutations were associated with increased TMB (P < 0.0001). The mRNA expression of STAT1 and CD4 was higher in patients with PTPRD/PTPRT mutant type than PTPRD/PTPRT wild type. Gene Set Enrichment Analysis revealed prominent enrichment of signatures related to inflammatory response, interferon gamma response and antigen processing and presentation in patients with PTPRD/PTPRT mutation. Conclusions: Our results suggest that PTPRD/PTPRT mutation is associated with better PFS and OS in NSCLC patients receiving ICIs by increasing immune-related gene signatures. The role of PTPRD/PTPRT in immunotherapy is needed to be further studied.

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Association Between FSIP2 Mutation and an Improved Efficacy of Immune Checkpoint Inhibitors in Patients With Skin Cutaneous Melanoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.629330 ◽

2021 ◽

Vol 8 ◽

Author(s):

Haoxuan Ying ◽

Anqi Lin ◽

Junyi Liang ◽

Jian Zhang ◽

Peng Luo

Keyword(s):

Immune Checkpoint ◽

Cutaneous Melanoma ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Response To Treatment ◽

Interacting Protein ◽

Tumor Immunogenicity

BackgroundImmune checkpoint inhibitors (ICIs) have shown remarkable success in treating skin cutaneous melanoma (SKCM); however, the response to treatment varies greatly between patients. Considering that the efficacy of ICI treatment is influenced by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential to predict the efficacy of ICI treatment.MethodsPatient data were collected from an ICI treatment cohort (n = 120) and a The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data were divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to FSIP2 mutation status. In this study, we analyzed the patients’ overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the efficacy of immunotherapy.ResultsThe efficacy of ICI treatment of SKCM patients with FSIP2 mutation was significantly better than that of patients without FSIP2 mutation. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group.ConclusionOur research suggests that the FSIP2 gene has the potential to predict the efficacy of ICI treatment. The high tumor immunogenicity and low Treg levels observed may be closely related to the fact that patients with FSIP2-MT can benefit from ICI treatment.

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Association Between FSIP2 Mutation and an Improved Prognosis in Patients With Skin Cutaneous Melanoma Treated With Immune Checkpoint Inhibitors

10.21203/rs.3.rs-52494/v1 ◽

2020 ◽

Author(s):

Haoxuan Ying ◽

Anqi Lin ◽

Jian Zhang ◽

Peng Luo

Keyword(s):

Immune Checkpoint ◽

Cutaneous Melanoma ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Response To Treatment ◽

Interacting Protein ◽

Tumor Immunogenicity

Abstract Background Immune checkpoint inhibitors (ICIs) have been remarkably successful in skin cutaneous melanoma (SKCM), however the response to treatment varies greatly among different patients. Considering that the efficacy of ICI treatment is affected by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential as a predictor of ICI treatment prognosis. Methods Patient data were collected from an ICI treatment cohort (n = 120) and The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data was divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to the FSIP2 mutation status. In this study we analyzed the patients’ overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the prognosis of immunotherapy. Results The prognosis of SKCM patients with FSIP2-MT receiving ICIs was significantly better than that of those with FSIP2-WT. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group. Conclusion Our research suggests that the FSIP2 gene has the potential to predict the prognosis of ICI treatment. The higher tumor immunogenicity and lower Treg levels may be closely related to the fact that patients with FSIP2-MT can benefit more from ICI treatment.

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An Immune Panel Signature Predicts Prognosis of Lung Adenocarcinoma Patients and Correlates With Immune Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.797984 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuan Zhou ◽

Lu Tang ◽

Yuqiao Chen ◽

Youyu Zhang ◽

Wei Zhuang

Keyword(s):

Lung Adenocarcinoma ◽

Risk Score ◽

Human Life ◽

Enrichment Analysis ◽

Progression Free Survival ◽

Roc Curves ◽

Gene Set Enrichment Analysis ◽

Sequencing Data ◽

Immune Microenvironment ◽

Immune Genes

Background: Lung cancer, especially lung adenocarcinoma (LUAD) with high incidence, seriously endangers human life. The immune microenvironment is one of the malignant foundations of LUAD, but its impact at the molecular level is incompletely understood.Method: A total of 34 LUAD samples from Xiangya Hospital were collected for immune oncology (IO) profiling. Univariate Cox analysis was performed to profile prognostic immune genes based on our immune panel sequencing data. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to construct a risk signature. The cut-off threshold of risk score was determined using X-tile software. Kaplan–Meier survival curves and receiver operating characteristic (ROC) curves were employed to examine the performance of this risk signature for predicting prognosis. The immune infiltration was estimated using a single-sample gene set enrichment analysis (ssGSEA) algorithm.Result: Thirty-seven immune genes were profiled to be significantly correlated with the progression-free survival (PFS) in our cohort. Among them, BST2, KRT7, LAMP3, MPO, S100A8, and TRIM29 were selected to construct a risk signature. Patients with a higher risk score had a significantly shorter PFS (p = 0.007). Time-dependent ROC curves indicated that our risk signature had a robust performance in accurately predicting survival. Specifically, the 6-, 12-, and 18-month area under curve (AUC) was 0.800, 0.932, and 0.912, respectively. Furthermore, the risk signature was positively related to N stage, tumor stage, and tumor malignancy. These results were validated using two external cohorts. Finally, the risk signature was significantly and uniquely correlated with abundance of neutrophil.Conclusion: Our study revealed an immune panel-based signature that could predict the prognosis of LUAD patients and was associated with the infiltration of neutrophils.

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High CTHRC1 expression may be closely associated with angiogenesis and indicates poor prognosis in lung adenocarcinoma patients

Cancer Cell International ◽

10.1186/s12935-019-1041-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Yangshan Chen ◽

Yu Sun ◽

Yongmei Cui ◽

Yiyan Lei ◽

Neng Jiang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Predictive Model ◽

Tumor Angiogenesis ◽

Poor Prognosis ◽

Cox Regression ◽

Enrichment Analysis ◽

Progression Free Survival ◽

Gene Set Enrichment Analysis ◽

Cox Regression Analysis ◽

Potential Biomarker

Abstract Background This study aimed to investigate the prognostic value of the potential biomarker collagen triple helix repeat containing 1 (CTHRC1) in lung adenocarcinoma (LUAD) patients. Methods A total of 210 LUAD patients diagnosed between 2003 and 2016 in the Department of Pathology of the First Affiliated Hospital of Sun Yat-sen University were included in this study. The expression of CTHRC1 and vascular endothelial growth factor (VEGF), and microvessel density (MVD, determined by CD34 immunostaining) were evaluated by immunohistochemistry in LUAD tissues. The association between the expression of these proteins and clinicopathological features or clinical outcomes was analyzed. Results Here, we confirmed that CTHRC1 expression was associated with prognosis and can serve as a significant predictor for overall survival (OS) and progression-free survival (PFS) in LUAD. Additionally, we observed that CTHRC1 expression was positively associated with tumor angiogenesis markers, such as VEGF expression (P < 0.001) and MVD (P < 0.01). Then, we performed gene set enrichment analysis (GESA) and cell experiments to confirm that enhanced CTHRC1 expression can promote VEGF levels. Based on and cox regression analysis, a predictive model that included CTHRC1, VEGF and MVD was constructed and confirmed as a more accurate independent predictor for OS (P = 0.001) and PFS (P < 0.001) in LUAD than other parameters. Conclusions These results demonstrated that high CTHRC1 expression may be closely related to tumor angiogenesis and poor prognosis in LUAD. The predictive model based on the CTHRC1 level and tumor angiogenesis markers can be used to predict LUAD patient prognosis more accurately.

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Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy

Cancer Gene Therapy ◽

10.1038/s41417-021-00422-5 ◽

2022 ◽

Author(s):

Fan Kou ◽

Lei Wu ◽

Ye Zhu ◽

Baihui Li ◽

Ziqi Huang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

The Cancer Genome Atlas ◽

Whole Exome ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Nsclc Patients

AbstractSomatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.

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Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.767694 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hang Chen ◽

Zeyang Hu ◽

Menglu Sang ◽

Saiqi Ni ◽

Yao Lin ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Risk Score ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Low Risk ◽

Immune Functions ◽

Mutational Burden ◽

Tumor Immune Microenvironment ◽

Tumor Mutational Burden ◽

Risk Patients

Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

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Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients’ survival

Scientific Reports ◽

10.1038/s41598-020-79907-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Woon Yong Jung ◽

Kyueng-Whan Min ◽

Young Ha Oh

Keyword(s):

Immune Response ◽

Survival Analysis ◽

Lung Adenocarcinoma ◽

Survival Rates ◽

Treatment Strategies ◽

Enrichment Analysis ◽

Genetic Alterations ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Solid Type

AbstractThe histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

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Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽

10.3390/biomedicines9030304 ◽

2021 ◽

Vol 9 (3) ◽

pp. 304

Author(s):

Marta Araujo-Castro ◽

Eider Pascual-Corrales ◽

Javier Molina-Cerrillo ◽

Teresa Alonso-Gordoa

Keyword(s):

Adrenocortical Carcinoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Progression Free Survival ◽

Mechanisms Of Resistance ◽

Response Efficacy ◽

Predictors Of Response ◽

Primary Endpoints ◽

Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

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