Predictors of response and resistance to checkpoint inhibitors in solid tumors

Rao, Sanjana; Moran, Amy E.; Graff, Julie N.

doi:10.21037/atm.2017.09.35

Cited by 9 publications

(6 citation statements)

References 22 publications

(16 reference statements)

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“…The mechanism of HNSCC recurrence is not fully understood to date. Emerging evidence suggests that the amount, type, and levels of activation of tumor-infiltrating lymphocytes are associated with response to conventional therapy and immunotherapy or survival [12][13][14][15][16][17][18] . For example, a recent multi-omics study carried out on HPV − HNSCC identified actin dysregulation and immunosuppression, due to widespread deletion of immune regulatory genes, as important determinants of disease pathology and response to treatment 19 .…”

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confidence: 99%

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

et al. 2022

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Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the human papillomavirus (HPV+)-driven subtype is the fastest rising cancer in North America. Although most cases of HPV+ HNSCC respond favorably to the treatment via surgery followed by radiochemotherapy, up to 20% recur with a poor prognosis. The molecular and cellular mechanisms of recurrence are not fully understood. Methods To gain insights into the mechanisms of recurrence and to inform patient stratification and personalized treatment, we compared the proteome and phosphoproteome of recurrent and non-recurrent tumors by quantitative mass spectrometry. Results We observe significant differences between the recurrent and non-recurrent tumors in cellular composition, function, and signaling. The recurrent tumors are characterized by a pro-fibrotic and immunosuppressive tumor microenvironment (TME) featuring markedly more abundant cancer-associated fibroblasts, extracellular matrix (ECM), neutrophils, and suppressive myeloid cells. Defective T cell function and increased epithelial-mesenchymal transition potential are also associated with recurrence. These cellular changes in the TME are accompanied by reprogramming of the kinome and the signaling networks that regulate the ECM, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Conclusions In addition to providing systems-level insights into the molecular basis of recurrence, our work identifies numerous mechanism-based, candidate biomarkers and therapeutic targets that may aid future endeavors to develop prognostic biomarkers and precision-targeted treatment for recurrent HPV+ HNSCC.

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confidence: 99%

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

et al. 2022

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“…Historically, management of patients with GI malignancies has been multimodality treatment using surgery and cytotoxic and targeted therapies [15]. More recently, immunotherapy has proved beneficial in a number of GI cancers; however, response is often dependent on various tumor-specific factors [16,17]. Commonly used biomarkers that are predictive of response include PD-L1 status, microsatellite stability (including the presence of POLE-D or E mutations), and tumor mutational burden [16].…”

Section: Discussionmentioning

confidence: 99%

The Impact of Poorly Differentiated Histology on Immunotherapy in Advanced Gastrointestinal Cancers

et al. 2023

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Introduction Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have shown a correlation between immune cell infiltration and poorly differentiated cancers. This study evaluated the impact of poorly differentiated histology on survival in patients with advanced gastrointestinal cancers treated with immunotherapy. Methods This study was a retrospective, single-center analysis of patients with gastrointestinal cancers treated with checkpoint inhibitors between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor and patient characteristics, progression free survival, and overall survival. Results A total of 123 patients were eligible and included in the analysis. Median age was 66 years (23-88 years). Majority had stage IV disease (89%), were white (65.5%), and were male (64.5%). Most common diagnoses were hepatocellular carcinoma (30.5%), gastric adenocarcinoma (16.5%) ,esophageal adenocarcinoma (17%) and colorectal cancer (19.8%). About 32% of the tumors were microsatellite instability-high (MSI-HIGH/DMMR), with BRAF V600E mutation rate of 10%. About 25% of the patients received checkpoint inhibitors as initial treatment while 35.5% had received two or more prior lines of therapy. Compared with well and moderately differentiated histology, patients with poorly differentiated tumors had a shorter median overall survival (mOS) (not reached [NR] vs. NR vs. 9.3 months, p=0.0264). There was no statistically significant difference in median progression free survival between histology types (2.5 vs.4.2 vs. 2 months, p=0.1314). On univariate survival analysis, moderately differentiated tumors correlated with a significantly longer mOS (HR: 0.48, CI: 0.24-0.93, p=0.030) and mPFS (HR: 0.62, 95%CI: 0.38-1.00, p=0.048) compared to poorly differentiated histology. Female patients (HR: 0.55, 95%CI: 0.34-0.90, p=0.018) and Eastern Cooperative Oncology Group (ECOG) of 1 (vs. ≥2) had significantly longer mPFS (HR: 0.58, 95%CI: 0.35-0.97, p=0.036). ECOG of 1 also correlated with longer mOS (HR: 0.47, 95%CI: 0.23-0.94, p=0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, 95%CI: 2.41-13.63, p<0.001) and mOS (HR: 5.45, 95%CI: 1.64-18.12, p=0.006). The number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, 95%CI: 1.03-1.39, p=0.022) and mOS (HR: 1.23, 95%CI: 1.01-1.50, p=0.045). On multivariable analyses, ECOG status of 0/1 vs. ≥2 and MSI-HIGH/DMMR vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with histologic differentiation status, race or mutations such as BRAF V600E or KRAS.

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“…As discussed above, there are several characteristics intrinsic to tumor cells that lead to primary resistance to checkpoint inhibitors. However, features of the tumor microenvironment and immune system are also associated with decreased or absent response to checkpoint inhibitor therapy [ 95 , 96 ] . Patients with notable responses to these drugs tend to have higher densities of CD8+ T-cells in the melanoma tumor prior to treatment [ 97 , 98 ] .…”

Section: Mechanisms Of Primary Resistance Associated With the Tumor M...mentioning

confidence: 99%

Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors

Fenton¹,

Sosman²,

Chandra³

2019

CDR

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Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system's ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient's native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

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Predictors of response and resistance to checkpoint inhibitors in solid tumors

Cited by 9 publications

References 22 publications

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

The Impact of Poorly Differentiated Histology on Immunotherapy in Advanced Gastrointestinal Cancers

Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors

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