Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

Kim, Jin K.; Chen, Chin-Tung; Keshinro, Ajaratu; Khan, Asama; Fırat, Canan; Vanderbilt, Chad; Segal, Neil H.; Stadler, Zsofia K.; Shia, Jinru; Balachandran, Vinod P.; Weiser, Martin R.

doi:10.1080/2162402x.2022.2054757

Cited by 5 publications

(4 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…300,524 A library of TCRs that specifically target shared neoantigens in an HLA-specific manner has subsequently been developed for patients with advanced cancers. 446,[525][526][527][528][529][530] As more public neoantigens and corresponding TCRs are discovered, more patients with frequent genetic alterations that drive cancers will benefit from the public neoantigen-reactive TCR library. In addition, the widespread use of cancer genome sequencing and neoantigen prediction pipelines will facilitate matching patients with therapies that target the public neoantigens of their tumors.…”

Section: Determination and Monitoring Of Neoantigen-specific T Cell R...mentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

317

150

View full text Add to dashboard Cite

Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.

show abstract

Section: Determination and Monitoring Of Neoantigen-specific T Cell R...mentioning

confidence: 99%

Neoantigens: promising targets for cancer therapy

Xie

Shen

Gao

et al. 2023

Sig Transduct Target Ther

317

150

View full text Add to dashboard Cite

show abstract

“…The density of TILs is frequently high in MSI-H tumors, in right-sided colon tumors, and in tumors that harbor a BRAF mutation. The presence of more abundant TILs in MSI-H tumors can be explained by the production of neoantigens consequent to an impaired DNA damage repair system [ 2 , 21 ]. The absence of data on MSI and BRAF status is a limitation of this study; this information was not available in the pathological reports as these measures were not assessed routinely during the study period.…”

Section: Discussionmentioning

confidence: 99%

Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer

Vitorino¹,

Eiriz²,

Tomás³

et al. 2022

Cureus

View full text Add to dashboard Cite

The tumor microenvironment is crucial in tumourigenesis, response to therapy, and elimination of tumor cells. Tumor-infiltrating lymphocytes (TILs) promote the host immune response and are associated with a better prognosis in colorectal cancer (CRC). This multicentric retrospective study evaluated the relationship between the presence and intensity of TILs and survival outcomes. A total of 651 patients from four Portuguese oncological centers who underwent surgical resection for stages II or III colorectal adenocarcinoma between 2016 and 2019 were included in this study. The mean age of the study population was 70 years; 58.2% were males. The median overall survival was 58.03 ± 1.29 months (95% confidence interval (CI) 55.50 -60.56), and the median disease-free survival (DFS) was 53.02 ± 1.39 months (95% CI 50.29 -55.74). Patients with high infiltrate (including those with moderate, abundant, or Crohn-like infiltrate) had significantly longer DFS i.e., 58.48 ± 1.84 months (95% CI 54.87 -62.09 months) vs 49.22 ± 1.75 months (95% CI 45.79 -52.64 months) in the group with absent or minimal infiltrate; p = 0.003. Assessing the side of the tumor, high infiltrate was associated with higher DFS (59.86 ± 2.36 months (95% CI 55.23 -64.50 months) vs 49.60 ± 2.40 months (95% CI 44.90 -54.29 months), p = 0.011). This work reinforces the importance of research into possible prognostic and predictive factors in patients with CRC.

show abstract

“…It is imperative to note that under high TMB, T cells are clonally expanded in MMRd with high TILs. The constraints of low TMB in MMRp made both TILs low and TILs high tumor uniform in their clonal expansion program, and they maintained similar TCR diversity ( 37 ). These findings show that T cell clonal dynamics in TMB with a low and high background may reciprocally impact immunosurveillance.…”

Section: Mechanistic Constraints Of Mmrp Tumors and Strategies Revers...mentioning

confidence: 99%

Mismatch repair-proficient tumor footprints in the sands of immune desert: mechanistic constraints and precision platforms

Majumder,

Nataraj,

Maitreyi

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL-17-TGF-β signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment. Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC. The emerging opportunities discussed in this review can turn the tide in favor of fighting the treatment dilemma for this elusive cancer.

show abstract

Intratumoral T-cell repertoires in DNA mismatch repair-proficient and -deficient colon tumors containing high or low numbers of tumor-infiltrating lymphocytes

Cited by 5 publications

References 37 publications

Neoantigens: promising targets for cancer therapy

Neoantigens: promising targets for cancer therapy

Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer

Mismatch repair-proficient tumor footprints in the sands of immune desert: mechanistic constraints and precision platforms

Contact Info

Product

Resources

About