Dados do Trabalho

Título

IgG-rich tertiary lymphoid structures promote immunotherapy response in gastric adenocarcinomas

Introdução

Ectopic lymphoid aggregates, known as tertiary lymphoid structures (TLSs), have been identified in a range of solid tumors, varying in density across patients. When fully mature, TLSs resemble tonsil and lymph nodes, with a central zone composed by B and dendritic cells, surrounded by a mantle of T cells. Recent work by our group (Kinker et al., 2023) and others have revealed that mature TLSs can generate antitumor adaptive immunity in situ by supporting the activity of tumor-reactive T cells and the differentiation of B cells into antibody-secreting plasma cells.

Objetivo

As plasma cells differentiate, they acquire the ability to produce specific antibody isotypes. Since antibody classes differ in their capability to mediate tumor cell clearance, here, we investigated whether the profile of plasma cells generated within TLSs is associated with the efficiency of antitumor immune responses in gastric adenocarcinomas.

Métodos

We analyzed paired H&E-stained slides and RNA-seq data from 375 gastric adenocarcinomas in The Cancer Genome Atlas (TCGA) cohort, as well as, RNA-seq data from 45 pre-treatment biopsies of metastatic patients that received immunotherapy with anti-PD1 as salvage treatment (clinical trial NCT#02589496).

Resultados

Analysis of TCGA data revealed that TLS+ tumors (n = 61) are divided into two main groups with distinct proportion of antibody isotype subclasses. Approximately half of TLS+ tumors showed a predominance of IGHA1/2 transcripts, resembling the pattern found in the normal stomach mucosa. Their counterparts, on the other hand, were enriched with IGHG1 transcripts and exhibited an increased IgG/IgA ratio. Importantly, TLS+ tumors with IgG profile had higher expression of IFN response genes when compared to TLS+ tumors with IgA profile and TLS- tumors. These data indicate that the maturation of high-affinity antibodies and isotype switching to IgG may occur in TLS-associated plasma cells specifically during pro-inflammatory processes. Among all immunoglobulin subclasses, IgG1 is of primary importance due to its ability to trigger antibody-dependent cellular cytotoxicity, phagocytosis and activation of the complement cascade. In line with that, we showed that an increased TLS signature score accompanied by a high IgG/IgA ratio, indicative of IgG-rich TLSs, was associated with improved outcomes in metastatic patients treated with anti-PD1.

Conclusões

Our data indicate that TLSs found in gastric adenocarcinomas may produce plasma cells with different antibody profiles, depending on signals received by the surrounding microenvironment. More importantly, we showed that inferring the presence of IgG-rich TLSs using gene expression data may guide the selection of patients that are more likely to respond to immunotherapy with immune checkpoint inhibitors. This strategy bypasses the need of high-quality tumor slides to assess TLSs, and can be used even when limited amounts of sample are available (e.g. biopsies).

Palavras-chave

Immunotherapy, tertiary lymphoid structure, antibody isotype

Financiador do resumo

FAPESP 19/25129-2 (fellowship to G.S.K.), 18/14034-8 (grant to T.S.M).