Mismatch repair-deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade.
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ABSTRACT:
SUBMITTER: Sena LA
PROVIDER: S-EPMC8327884 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.
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Project description:: More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers.Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade.
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Project description:Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable, but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Among 121 advanced dMMR mCRC patients treated with CPI at 2 institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on preoperative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggest that residual radiographic tumor may not require systematic resection following response to anti-PD1-based therapy. However, larger prospective studies are warranted.
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Project description:Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.
| S-EPMC11372054 | biostudies-literature
Project description:Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. All patients completed treatment without severe toxicity. A partial radiologic response was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on Magnetic Resonance Imaging (MRI). Pathologic response was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. Monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.
2024-07-19 | GSE268903 | GEO
Project description:Non-T-cell-inflamed immunologically "cold" tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB) and can be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis, and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Rb loss was enriched in non-T-cell-inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I IFN signaling within tumor cells, resulting in differential macrophage and T-cell-mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.
| S-EPMC10239341 | biostudies-literature
Project description:BackgroundMismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.MethodsWe confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.ResultsWe identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.ConclusionsWe demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
| S-EPMC10124306 | biostudies-literature
Project description:Wide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is largely unknown. Using anti-PD1 and anti-LAG-3 ICI treatments, we here investigated the effect of bone marrow hematopoiesis in tumor-bearing Msh2loxP/loxP;TgTg(Vil1-cre) mice. The OS under anti-PD1 antibody treatment was 7.0 weeks (vs. 3.3 weeks and 5.0 weeks, control and isotype, respectively). In the anti-LAG-3 antibody group, OS was 13.3 weeks and thus even longer than in the anti-PD1 group (p = 0.13). Both ICIs induced a stable disease and reduced circulating and splenic regulatory T cells. In the bone marrow, a perturbed hematopoiesis was identified in tumor-bearing control mice, which was partially rescued by ICI treatment. In particular, B cell precursors and innate lymphoid progenitors were significantly increased upon anti-LAG-3 therapy to levels seen in tumor-free control mice. Additional normalizing effects of ICI treatment were observed for lin-c-Kit+IRF8+ hematopoietic stem cells, which function as a "master" negative regulator of the formation of polymorphonuclear-myeloid-derived suppressor cell generation. Accompanying immunofluorescence on the TME revealed significantly reduced numbers of CD206+F4/80+ and CD163+ tumor-associated M2 macrophages and CD11b+Gr1+ myeloid-derived suppressor cells especially upon anti-LAG-3 treatment. This study confirms the perturbed hematopoiesis in solid cancer. Anti-LAG-3 treatment partially restores normal hematopoiesis. The interference of anti-LAG-3 with suppressor cell populations in otherwise inaccessible niches renders this ICI very promising for subsequent clinical application.
| S-EPMC10312035 | biostudies-literature
Project description:BackgroundNeoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.MethodsWe initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.ResultsA total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.ConclusionsMismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
| S-EPMC9492301 | biostudies-literature