Background
DNA repair is necessary to ensure cellular genome integrity, served as a multi-enzyme, multi-pathway system [
1]. DNA damage can occur either through errors during DNA replication or through chemical changes in base nucleotides in the cellular environment. Several mechanisms such as nucleotide excision repair (NER), base excision repair (BER), DNA strand break repair (DSBR), direct reversal of DNA damage, and replication of DNA damage by specialized DNA-derived polymerases (bypass replication), which are fundamental underlying mechanisms in different DNA repair pathways [
2]. The occurrence of many specific human diseases is thought to be related to these defects in the repair pathways. In addition, previous studies have long found that the repair of damaged DNA is closely related to a variety of cellular processes such as DNA replication, DNA recombination, and cell cycle checkpoint arrest.
Mismatch repair (MMR) genes produced by DDR pathway is the most known type of DNA mutation cause [
3]; it is although to regulate multiple DNA-related processes, such as DNA stability and alternative splicing [
4]. Recently, aberrant expression of MMR regulators is revealed to be associated with cancer and immune events including tumorigenesis, immunomodulatory (IM) abnormality and malignant tumor progression [
5].
Neoadjuvant chemotherapy is a treatment method in which some cycles of chemotherapy are given before tumor resection and the remaining cycles are given after surgery. Neoadjuvant chemotherapy is considered as a therapy with multiple potential benefits in the treatment of lung cancer [
6]. For patients with one of these types of tumors that do not respond well to chemotherapy, the value of that treatment is diminished if therapeutic interventions to improve outcomes for such patients cannot be identified.
The association involving mismatch repair (MMR) genes, molecular subtype and specific immune cell group in tumor microenvironment has been focused by more recent studies. Its prognosis value in lung adenocarcinoma (LUAD) neoadjuvant chemotherapy remains elusive. In this investigation, we integrated the clinical and molecular data of 461 TCGA-LUAD and 103 Chinese LUAD cancer patients to comprehensively evaluate the MMR modification patterns and with lung cancer neoadjuvant chemotherapy. Distinct MMR modification regulation pattern and associated distinct immune characters, neoadjuvant chemotherapy sensitivity and prognoses were identified, showing the key roles of MMR gene pattern in the developments of individual TIME in lung adenocarcinoma patients. We also construct a methodology to quantify the MMR modification of individual LUAD patients by evaluating the gene patterns of 24 MMR regulators.
Discussion
A growing number of studies have shown that MMR genes play critical roles in tumorigenesis, therapeutic clinical resistance, and immune responses through the cooperation between MMR regulators [
4,
5]. At present, questions about the role of MMR modification patterns in the tumor immune microenvironment have been explored and answered in some cancer types. In this investigation, we further deepen our understanding of TIME-based antitumor immune responses by exploring and understanding the role of MMR gene patterns in the immune landscape of lung adenocarcinoma and use this as a springboard to provide more effective LUAD patients. immunotherapy strategies.
Lung cancer can already be subtyped based on genomic profiling, which promises to improve the application of precision-focused personalized therapy in the future [
12]. In this study, among 24 MMR regulators, four MMR-related clusters with significantly different immune microenvironments have been specified, based on their differences in aneuploidy, overall somatic copy number alterations, expression of immune-related genes and prognosis. In addition, Th17 expression is often associated with improved prognosis in previous studies [
13]. Coincidentally, this experiment also draws consistent conclusions as follows: C3 presents enriched pathways associated with complete immune activation and exhibits the most obvious Th17 signature. MMRcluster-C1 exhibited not only high proliferation and ITH, but also enriched pathways associated with full immune activation and relatively high CD8 + T cell infiltration, all of which indicate high tumor growth rates in C1. So, it may seem strange but not contradictory that C1 shows a state of activated immunity but at the same time there is a low survival rate. MMRcluster-C2 exhibits features that are primarily associated with immunosuppression of biological processes and relatively low infiltration of CD8 + T cells.
Because each individual has a different MMR modification pattern, we adopted a methodology called MMRscore to accurately calculate the MMR pattern of different lung adenocarcinoma patients. Our study also found that MMRScore was positively correlated with CNV. Through comprehensive analysis, we identified MMRScore as a potential independent prognostic factor for neoadjuvant chemotherapy. Therefore, we judged that the MMR gene pattern may serve as a key influencer leading to different clinical responses to immunotherapy and indirectly validated the value of MMRscore in predicting immunotherapy outcome.
The advent of anti-PD-1/PD-L1 ICT therapy is a breakthrough in the treatment of certain advanced cancer types [
14,
15]. However, LUAD patients who received this treatment did not all have a positive and significant clinical response, and immunotherapy results showed individual heterogeneity. Therefore, it is very important to find markers that can predict the outcome of immunotherapy. It is known that if people have pre-existing CD8 + T cell infiltration and high tumor mutational burden, they can have a higher response to anti-PD-1 therapy. However, in some advanced cancers, contrary to some known cancer types, tumor mutational burden, neoantigen burden, and HLA engagement did not correlate with response to anti-PD-1 therapy. And in other cancer type, immune-infiltrating tumors and immune-desert/excluded tumors, respectively, did not differ statistically in response or survival to anti-PD-1 therapy. In our study, we discovered and confirmed the prognostic value of MMRscore in cold-immunized LUAD patients with low T cell infiltration and used MMRscore as a predictive strategy for anti-PD-1/PD-L1 therapy.
Neoadjuvant chemotherapy can theoretically improve disease-free survival (DFS) and overall survival (OS) by early treatment of microscopic metastases. From a practical standpoint, neoadjuvant chemotherapy provides sufficient time for other surgical planning such as custom endoprosthesis preparation. In addition, neoadjuvant chemotherapy can make patients who would otherwise be inoperable and must have their limbs amputated eligible for surgery if they shrink the tumor sufficiently [
16]. At the same time neoadjuvant chemotherapy can improve postoperative healing because recovery from chemotherapy is less time-critical. One of the most important ways to improve prognosis is early identification combined with subsequent treatment. However, there are currently no known therapeutic interventions to improve outcomes for patients with poor histologic response to chemotherapy [
17]. Therefore, we believe that MMRscore has adjuvant predictive value for neoadjuvant chemotherapy.
Finally, this investigation discovered a link between MMR gene pattern, copy number variation (CNV), and the immunological landscape of lung cancer tumors. With a clinical cohort to verify our pre results on TCGA-LUAD, our in-depth analysis of MMR alteration patterns in individual lung cancer patients adds to knowledge of tumor immunological landscape and paves the way for neoadjuvant chemotherapy prognosis or novel and better immunotherapeutic methods. In our study, we have a disadvantage due to the lack of enough clinical data on immune checkpoint therapy. This is an important factor to consider, as it can limit the validity and applicability of the research findings.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.