Tumor-Infiltrating Lymphocytes in Colorectal Cancer: The Fundamental Indication and Application on Immunotherapy

The clinical success of immunotherapy has revolutionized the treatment of cancer patients, bringing renewed attention to tumor-infiltrating lymphocytes (TILs) of various cancer types. Immune checkpoint blockade is effective in patients with mismatched repair defects and high microsatellite instability (dMMR-MSI-H) in metastatic colorectal cancer (CRC), leading the FDA to accelerate the approval of two programmed cell death 1 (PD-1) blocking antibodies, pembrolizumab and nivolumab, for treatment of dMMR-MSI-H cancers. In contrast, patients with proficient mismatch repair and low levels of microsatellite stability or microsatellite instability (pMMR-MSI-L/MSS) typically have low tumor-infiltrating lymphocytes and have shown unsatisfied responses to the immune checkpoint inhibitor. Different TILs environments reflect different responses to immunotherapy, highlighting the complexity of the underlying tumor-immune interaction. Profiling of TILs fundamental Indication would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. In this review, we summarize phenotypic diversities of TILs and their connections with prognosis in CRC and provide insights into the subsets-specific nature of TILs with different MSI status. We also discuss current clinical immunotherapy approaches based on TILs as well as promising directions for future expansion, and highlight existing clinical data supporting its use.

A New Prognostic and Therapeutic Immune-related Risk Signature of Colorectal Cancer

BackgroundAlthough some advanced colorectal cancer (CRC) patients could select immunotherapy, but still most microsatellite stability (MSS) CRC patients did not respond. Our present study aims to set up a novel system for prognostic prediction and immunotherapeutic responsiveness for MSS CRC patients.MethodsUnivariable Cox regression survival analysis and least absolute shrinkage and selector operation (LASSO) regression analysis were performed to identify prognostic genes and establish immune risk signatures. Multivariate Cox regression analysis was performed to verify whether these clinical features could predict prognosis. R package was used to analyze the relationship between the immune-related risk model and these immune cells, effector molecules, and immune checkpoints.ResultsWe constructed an immune-related signature and verified its predictive capability. Immune-related signature included 12 differentially expressed IRGs (12 DE IR MSSGs), including CXCL1, CD36, FABP4, MS4A2, NRG1, VGF, GRP, HDC, XCL1, NGF, MAGEA1, and IL13. The signature consisting of 12 DE IR MSSGs was an independent and effective prognostic factor for the overall survival of CRC patients. In addition, the signature consisting of 12 DE IR MSSGs reflected the infiltration characteristics of different immunocytes in tumor immune microenvironment. The signature consisting of 12 DE IR MSSGs also had a significant correlation with immune checkpoint molecules.

Long-Term Survival of PD-1 Inhibitor Combined with Antiangiogenic Agents in a Patient with Pulmonary Sarcomatoid Carcinoma Complicated with Esophageal Cancer: A Case Resport and Literature Review

Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive rare subtype of non-small cell lung cancer (NSCLC). PSC is known for its poor prognosis and low sensitivity to conventional treatments such as chemotherapy, radiation, and adjuvant therapies. In recent years, the application of targeted therapy and immunotherapy in this field has made progress. Although programmed cell death 1 (PD-1) inhibitors have been reported to show favorable antitumor effects in PSC patients with high programmed death-ligand 1 (PD-L1) expression, the efficacy of PD-1 inhibitors in combination with antiangiogenic drugs has not been investigated. Here, we report for the first time a case of dual-source cancer with low expression of PD-L1 and microsatellite stability (MSS) which showed continuous response to sintilimab combined with anlotinib as first-line treatment and achieved a long progression free survival (PFS) of 24 months with no serious adverse reactions. This case presents a new therapeutic prospect for PSC and a potential to enhance its prognosis and treatment strategies.

Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report

BackgroundPancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.Case PresentationHere, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.ConclusionsThis outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.

Identification KCNE4 and DNASE1L3 for Prognostic Utility in Colorectal Cancer: A Bioinformatics Analysis

Objective: Immunotherapy has improved the prognosis of cancer patients who did not benefit from conventional treatment and decreased mortality, which has become an effective treatment for multiple carcinomas in their advanced stages. Patients with colorectal cancer (CRC) were mostly in the state of mismatch repair-proficient or microsatellite stability, with limited benefit in immunotherapy. Hence, immunotherapy strategies for CRC still need to be explored continuously. Methods: Based on comprehensive analysis of the immune infiltration associated genes in the Cancer Genome Atlas (TCGA) database and differential genes for the progression and metastasis of CRC in the Gene Expression Omnibus (GEO) database, as well as validation analysis on several online databases, we obtained two genes (KCNE4 and DNASE1L3) as novel immune-related molecules for CRC. Results: High expression of KCNE4 and DNASE1L3 were significantly correlated with CRC progression and prognosis, and were strongly associated with the infiltration of different types of macrophages in the CRC tumor microenvironment. In addition, we analysed the guidance value of KCNE4 and DNASE1L3 in anti-PD-1 therapy using data from the IMvigor210 group, and predicted the significant value of KCNE4 and DNASE1L3 in CRC immunotherapy by analyzing the correlation of KCNE4 and DNASE1L3 with the expression of CRC immune checkpoint markers. Conclusions: We hypothesized that DNASE1L3 and KCNE4 would be potential prognostic biomarkers and predictors of immunotherapy in CRC. Our results may serve as an indication of survival prognosis and provide a new assessment indicator for the choice of immunotherapy for CRC patients.

Efficacy and Safety of Fruquintinib Plus PD-1 Inhibitors Versus Regorafenib Plus PD-1 Inhibitors in Refractory Microsatellite Stable Metastatic Colorectal Cancer

BackgroundMicrosatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR.Materials and MethodsWe retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP.ResultsA total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time.ConclusionOur study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP.

The combination of Tislelizumab and apatinib obtained complete remission for alpha-fetoprotein-producing gastric cancer with microsatellite stability: case report

BackgroundAlpha‑fetoprotein (AFP)‑producing gastric cancer (AFPGC) is a rare type of gastric cancer with high metastasis rate and poor prognosis. Despite substantial progress in the treatment of many solid tumors, there are no reports of the safety and effectiveness of immune checkpoint inhibitor (ICI) in combination with anti-angiogenesis in AFPGC patients with microsatellite stability (MSS).Case presentationThis is a case of a 69-year-old man who was diagnosed with metastatic AFPGC. After the progression of resistance to chemotherapy, Tislelizumab combined with apatinib was attempted, although the patient was microsatellite stable. With 3 cycles of combination therapy, a partial remission (PR, shrunk by 56%) was obtained, and the quality of life improved significantly. Surprisingly, after more than one year of continuous application of the above treatment regimen, both the primary and metastatic tumors in this patient eventually disappeared, which achieved complete remission (CR) without surgery. Following the combined treatment, the patient had a progression-free survival of more than 16 months and now is still in continue to benefit. ConclusionsThis is the first report that we are aware of on the effective treatment of AFPGC with Tislelizumab in combination with Apatinib. This provides a highly effective and tolerable therapeutic strategy for microsatellite-stabilized AFPGC.