Immune surveillance genes in Diffuse large B-cell lymphoma

Madhavi Bhatia, National Institute of Pharmaceutical Education and Research Guwahati

Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma that represents approximately 25-35% of non-Hodgkin’s disease lymphomas. DLBCL is specified by a high degree of molecular heterogeneity and genetics that impacts patient stratification and also treatment response. After the first-line therapy with drugs, there are chances that 30-40% of cases may relapse or experience 15% primary refractory disease. The results of B-cell cancer treatment might be affected by somatic mutations of the cancer cells (intrinsic resistance), the genotype of individual patients, and treatment-selected resistant subpopulations (acquired resistance).CAR-T treatment has shown efficacy in refractory and relapsed DLBCL (rrDLBCL) but it is sometimes followed by severe adverse events such as cytokine release syndrome and neurological toxicity along with B-cell aplasia. 

Role of immune surveillance in diagnostic DLBCL

Immune surveillance involves the recognition of tumour cells by T-cells that require antigen presentation in association with MHC molecules. In the case of Natural killer cells, the cells recognize and attack the tumour cells with downregulated MHC class I molecules. In dDLBCL, there is frequent loss of expression of MHC I and MHC II molecules.

A study was conducted to understand the immune surveillance in dDLBCL and rrDLBCL. In the study, 30 dDLBCL and 17 rrDLBCL patients were included. In the case of rrDLBCL patients, about 15 patients relapsed within the first two years from diagnosis, and the remaining 2 patients relapsed after 4.7 and 6 years from diagnosis. There was only a significant difference in lactate dehydrogenase (LDH) among cured DLBCL patients and patients experiencing relapse or refractory disease.

Genome sequencing 

Whole–exome sequencing (WES) was done on 47 tumour samples. 58 genes encompass the major immune surveillance pathway in dDLBCL,rrDLBCL, and post-treatment patients. Out of these, genetic variation was seen in 48 genes. 242 somatic variants were observed in 48 affected immune surveillance genes. After filtering for quality, 147 nonsense, small frameshift, nonsynonymous, and splice variants in 36 immune surveillance genes were detected.

Mutational profile of immune surveillance genes

Genetic variations in at least one of 36 immune surveillance genes were observed in 22 dDLBCL and 13 rrDLBCL patients. The number of genetic variations in dDLBCL and rrDLBCL ranged from 1 to 19 and 1-12 per patient, respectively. The genetic variants which were detected in both, dDLBCL and rrDLBCL include mostly missense mutations. This was followed by nonsense and frameshifts. There was no difference in the distribution of mutation types in dDLBCL or rrDLBCL patients. 16 % of dDLBCL and 29% of rrDLBCL genetic variations were observed in genes that are involved in antigen presentation and 13% of dDLBCL and 12% of rrDLBCL had genetic variations in genes related to immune suppression and exhaustion. Antigen-presenting genes were mostly affected more in rrDLBCLs than dDLBCLs. Variant allele frequencies (VAFs) of the individual mutations within the affected genes differ between diagnostic and relapsed biopsies. No significant difference was observed in paired samples because the host does not respond or detect a difference in the tumour even if the IS genes are mutated and become invisible. In the mutational profile of the immune surveillance gene, a significant difference is observed only in the proportion of Macrophages (M1) between dDLBCLs and rrDLBCLs and genes related to antigen presentation.

Future prospects-

After understanding the role of genetic variation in immune surveillance genes present in the dDLBCL and rrDLBCL patients. Thus, in future treatment strategies for DLBCL might target multiple immune escape pathways along with conventional chemotherapy.

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Reference– Nesic, M., Sønderkær, M., Brøndum, R.F. et al. The mutational profile of immune surveillance genes in diagnostic and refractory/relapsed DLBCLs. BMC Cancer 21, 829 (2021). https://doi.org/10.1186/s12885-021-08556-3

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About the author- Madhavi Bhatia is currently pursuing a Master of Science in Pharmaceutical Biotechnology from NIPER, Guwahati. Her area of interest lies in understanding the role of gene mutation in the development of various diseases and developing a treatment for such diseases.