PD-L1 regulation in colorectal cancer and role of DNA damage induced by chemotherapies

2020 ◽  
pp. 1-14
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Tumor Infiltrating Lymphocytes ◽  
Chemotherapeutic Agents ◽  
Immune Checkpoints ◽  
T Cell Infiltration ◽  
First Line Therapy ◽  
Response To Chemotherapy

For patients with metastatic colorectal cancer (CRC), first-line therapy is based on chemotherapeutic agents, such as oxaliplatin, 5-fluorouracil and irinotecan. These drugs increase the overall survival, but resistance to therapy appears in almost 90% of patients, and the 5-year survival rate for patients with metastatic CRC is only about 12%. During the last few years, immune checkpoints blockade therapies have been developed and show good response in different cancers, including CRC with microsatellite instability (MSI). In this CRC subtype, the response rate to anti-PD-(L)1 antibodies is high thanks to the presence of neoantigens and tumor-infiltrating lymphocytes that are associated with the anti-tumor immune response. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, have been approved for CRC MSI treatment. Moreover, it has been shown that the combination of chemotherapy and anti-PD-(L)1 molecules may convert cold tumors into hot tumors in which the immune system and T-cell infiltration are activated. In addition, recent studies found that DNA damage induces PD-L1 expression. ATM, ATR, DNA-PKcs and Chk1 are key sensors of the DNA damage response that regulate PD-L1 expression. This review summarizes the current knowledge on PD-L1 regulation at the genetic, epigenetic, transcriptional and translational levels. It also describes PD-L1 activation in response to chemotherapy and DNA damage. Then, it summarizes the current clinical trials that assess anti-PD-(L)1 therapies in combination with kinase inhibitors or chemotherapeutic agents in CRC.

Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 189-189
Author(s):  
Katherine Anne Johnson ◽  
Philip Emmerich ◽  
Kristina A. Matkowskyj ◽  
Dustin A. Deming
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Molecular Profile ◽  
High Power Field ◽  
Kras Mutations ◽  
T Cell Infiltration ◽  
The Impact

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p < 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p < 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.

scholarly journals Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 462 ◽  
Author(s):  
Kevin Chih-Yang Huang ◽  
Shu-Fen Chiang ◽  
William Tzu-Liang Chen ◽  
Tsung-Wei Chen ◽  
Ching-Han Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Dna Hypomethylation ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy ◽  
Clinical Benefits

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

Versican proteolysis as a key regulator of CD8+ T-cell infiltration in colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15082-e15082
Author(s):  
Dustin A. Deming ◽  
Chelsea Hope ◽  
Philip Emmerich ◽  
Adam Pagenkopf ◽  
Kristina Matkowskyj ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Staining Intensity ◽  
Cell Infiltration ◽  
Tissue Samples ◽  
Tumor Bed ◽  
T Cell Infiltration

e15082 Background: Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes (TILS) in the tumor bed may substantially augment clinical immunotherapy responses. Proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, with putative immunostimulatory activities. Methods: Matched normal and CRC tissue samples were collected from 122 patients with cancers across all stages and locations throughout the colon and rectum. These samples were stained for VCAN, αDPEAAE (neoepitope generated in cleaving VCAN to versikine), and CD8 and scored by a pathologist. Tumors were classified as VCAN proteolysis-predominant (VPP) if their staining for total VCAN staining intensity was < 1+ and staining for VCAN proteolysis (αDPEAAE antibody) was > 2. Conversely, tumors were classified as VCAN proteolysis-weak (VPW) if intact VCAN staining intensity was > 1+ or αDPEAAE intensity was < 2+. IHC for mismatch repair (MMR) proteins was also performed. Results: Overall increased VCAN staining was observed in cancer versus (vs) normal tissue. VPP tumors had a 10 fold greater infiltration of CD8+ T-cells vs VPW cancers (p < 0.001). The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in both cancers with proficient (p) MMR and deficient (d) MMR. In both pMMR and dMMR, the VPP tumors had the greatest degree of CD8+ T-cell infiltration (Wilcoxon rank sum tests: pMMR p = 0.006; dMMR p = 0.03). Among the VPP tumors there was a greater degree of CD8+ T cell infiltration in the dMMR cancers vs pMMR cancers (35 versus 14.8 TILs per high power filed, p = 0.04). Nuclear CTNNB1, a marker for activation of WNT signaling, negatively correlated with CD8+ T cell infiltration( p = 0.014). In addition, VCAN accumulation correlated with the presence of nuclear CTNNB1 (p < 0.001) Conclusions: This is the first description indicating that VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker.

scholarly journals Controlled Drug Delivery Vehicles in Veterinary Oncology: State-of-the-Art and Future Directions

Processes ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 541 ◽  
Author(s):  
Patricia de Faria Lainetti ◽  
Fernanda Zuliani ◽  
Antonio Fernando Leis-Filho ◽  
Ricardo Henrique Fonseca Alves ◽  
Carlos Eduardo Fonseca-Alves
Keyword(s):  
Drug Delivery ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Controlled Drug Delivery ◽  
Chemotherapeutic Agents ◽  
Drug Delivery Vehicles ◽  
Controlled Systems ◽  
Delivery Vehicles ◽  
Future Direction

Controlled drug delivery systems can be used to carry several anticancer agents, including classical chemotherapeutic agents such as doxorubicin, paclitaxel or cisplatin, and are also used for the encapsulation of tyrosine kinase inhibitors and monoclonal antibodies. Usually, the controlled systems are used to decrease drug toxicity, increase local drug concentration or target specific organs or systems. In dogs, liposomal doxorubicin is the most known controlled drug delivery vehicle in veterinary medicine. However, several antitumor drugs can be encapsulated within these systems. Since the delivery vehicles are a relatively new topic in veterinary oncology, this review aims to discuss the current knowledge regarding the controlled drug delivery vehicles and discuss the current challenges and future direction of its use in veterinary oncology.

Epigenetic regulation of immune checkpoints and T cell exhaustion markers in tumor-infiltrating T cells of colorectal cancer patients

Epigenomics ◽  
2020 ◽  
Vol 12 (21) ◽  
pp. 1871-1882
Author(s):  
Varun Sasidharan Nair ◽  
Reem Saleh ◽  
Salman M Toor ◽  
Rowaida Z Taha ◽  
Ayman A Ahmed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Histone 3 ◽  
Tumor Tissues ◽  
Colorectal Cancer Patients

Aim: To elucidate the epigenetic alterations behind the upregulation of immune checkpoints and T cell exhaustion markers in colorectal cancer (CRC) patients. Materials & methods: mRNA expressions of different immune checkpoint/exhaustion markers were analyzed by quantitative real-time reverse transcriptase PCR and epigenetic investigations were performed using bisulfite sequencing and chromatin immunoprecipitation quantitative PCR. Results: mRNA expressions of PD-1, TIM-3, CTLA-4, PD-L1 and TOX2 were significantly upregulated in CD4+ and CD8+ tumor-infiltrating lymphocytes and bulk CRC tumor tissues. Histone 3 lysine 9 trimethylation was downregulated and histone 3 lysine 4 trimethylation was upregulated in PD-L1 and TOX2 promoters in tumor tissues, suggesting that PD-L1 and TOX2 upregulation in CRC tumors could be mediated by activating histone 3 lysine 4 trimethylation. Conclusion: Epigenetic modifications in promoters of immune checkpoint and T cell exhaustion genes could induce their upregulation, and potentially implicate the use of epigenetic modifiers to enhance antitumor immunity in CRC patients.

Immune infiltrates in liver metastases of colorectal cancer and response to chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15069-e15069 ◽  
Author(s):  
N. Halama ◽  
S. Michel ◽  
M. Kloor ◽  
I. Zoernig ◽  
T. Pommerencke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Immune Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Marker ◽  
Response To Therapy ◽  
Time To Progression ◽  
Antibody Treatment ◽  
Primary Tumors ◽  
Response To Chemotherapy

e15069 Background: Colorectal cancer (CRC) is a major cause of death from cancer. Patients with irresectable or metastasized CRC usually receive chemotherapy in combination with a monoclonal antibody, median overall survival time is around 20- 21 months with response rates of around 50%. Almost half of the patients experience treatment related side effects without benefit. K-ras mutation is the only (negative) predictive marker for response to therapy (for EGFR-targeting antibody treatment), no biomarkers are available that help to select patients most likely responding to chemotherapy. In primary colon cancer immune infiltrates in the tumor represent an important prognostic factor. High densities of tumor infiltrating lymphocytes (TIL) were shown to be correlated with an improved survival in patients with primary CRC. TILs therefore represent a valuable prognostic tool, a high density of immune cells being associated with good outcome independently of other established prognostic markers. Little is known about an association between these immune cells and the response to chemotherapy. Methods: Here the relation between infiltrates of immune cells in liver metastases of CRC and the response to chemotherapy (using immunohistochemical staining against CD8, GranB, FOXP3, CD45RO, etc.) was investigated. Samples from 33 patients with metastasized colorectal cancer (samples from 22 patients were used as training set and samples from 11 patients as validation set) were analyzed. Results: The evaluation of positively stained TIL in the invasive margin of the liver metastasis allowed to predict response to chemotherapy. This was also observed in the analysis of the time to progression, where higher numbers of positively stained cells were associated with longer intervals. The difference between the groups with either response or no response to chemotherapy in time to progression was statistically significant in the analyzed sets (Mann-Whitney- U, p<0.001, two-tailed, z=-3,961, n=33). In primary tumors no association between TIL densities and response to chemotherapy was observed. Conclusions: Our results suggest that the immune system has an important impact on the efficacy of chemotherapy and the presented data will have implications for the assessment of therapy options. No significant financial relationships to disclose.

scholarly journals Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1941
Author(s):  
Davide Ciardiello ◽  
Giulia Martini ◽  
Vincenzo Famiglietti ◽  
Stefania Napolitano ◽  
Vincenzo De Falco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Clinical Activity ◽  
First Line ◽  
First Line Therapy ◽  
Novel Biomarkers ◽  
Third Line

The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.

Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 529-529 ◽  
Author(s):  
Priyanka Sharma ◽  
William E. Barlow ◽  
Andrew K. Godwin ◽  
Laura A Knight ◽  
Steven M. Walker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cox Regression ◽  
Early Stage ◽  
Selection Criterion ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Signature ◽  
Molecular Signature ◽  
Response To Chemotherapy ◽  
Damage Response

529 Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.

A phase Ib study combining irinotecan with AZD1775, a selective WEE 1 kinase inhibitor, in RAS/RAF mutated metastatic colorectal cancer patients who progressed on first line therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3627-TPS3627 ◽  
Author(s):  
Deirdre Jill Cohen ◽  
Elda Grabocka ◽  
Dafna Bar-Sagi ◽  
Robert Godin ◽  
Lawrence P. Leichman
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Pharmacokinetic Parameters ◽  
First Line ◽  
Phase Ib ◽  
First Line Therapy ◽  
Line Therapy ◽  
Expansion Cohort

TPS3627 Background: Mutant KRAS tumors show a dependency on WT-H/N-Ras for activation of ATR/Chk1-mediated G2 DNA damage response (Grabocka, Cell, 2015). We have shown in vitro that the Wee1 kinase inhibitor AZD1775, which acts to abrogate the G2 DNA damage checkpoint and induces replication stress during S-phase, selectively sensitizes RAS/RAF mutant cells to the DNA damaging agent irinotecan. Up to 65% of metastatic colorectal cancers harbor RAS or BRAF mutations and these patients have limited treatment options following first line therapy. Methods: This is an open label, single-arm, phase Ib study using a modified 3+3 dose-escalation schedule with expansion cohort. Primary objective is to determine the MTD of AZD1775 in combination with irinotecan as 2nd-line therapy in patients with metastatic KRAS, NRAS or BRAF mutated colorectal cancer. Up to 18 patients will be enrolled in the dose escalation portion. Standard dose irinotecan is given on day 1 of every 2 week cycle. AZD1775 is administered PO twice daily for 3 to 5 days of each cycle, starting cycle 2. The maximum tolerated dose (MTD) is defined as the highest dose level at which ≤1 of 6 patients experience a dose limiting toxicity. Once the MTD is reached and/or recommended dose for expansion is determined, a dose expansion cohort of 14 patients will be enrolled. Secondary endpoints include characterizing the safety profile at the MTD, obtaining a preliminary estimate of efficacy for the combination (measured by overall response rate, progression-free and overall survival rates), and obtaining pharmacokinetic parameters. Pre- and on-treatment biopsies will be collected from the expansion cohort to determine: adequate target engagement of Wee1, changes in markers of DNA damage, TP53 mutation status, and changes in gene expression profiles in order to identify potential biomarkers of response. At February 2017, 2 patients have been enrolled on this study. Clinical trial information: NCT02906059. [Table: see text]

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