Disruptions in antigen processing and presentation machinery on sarcoma

Abstract

Background: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients.

Methods: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.

Results: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.

Conclusion: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.

Keywords: Antigen Processing Machinery; Distant Metastasis; HLA Class I; Personalized Therapy; Sarcoma.

Fig. 1

Probability of APM’s presence among sarcoma histotypes. Rows are the histotype, and columns are the APM protein evaluated. Each figure shows the density (solid lines) of the probability of finding APM protein and the mean value (dashed vertical lines). LMP10 in UPS has most of the probability mass (i.e., the density)—as well as the mean—over 0.95; it is hence very unlikely to find defects in LMP10 in UPS. On the contrary, LMP10 in LMS can be defective in a substantial fraction of cases; similarly, MHC I transporting unit TAP2 was likely to be defective in UPS, GIST and HLA Class I subunit α (HC10) in CHS

Fig. 2

Spatial heterogeneity in the probability of APM’s presence among sarcoma histotypes. Rows are the histotype, and columns are the APM protein evaluated. Each figure shows the mean (line) and CI (shade) for each “core type” evaluated. HG, high grade; HI, high infiltrate; LG, low grade; HI, high infiltrate; TP, tumor periphery; TB: tumor border. See text for further details

Fig. 3

GIST, DDLPS, UPS and CHS lose APM in high-grade areas. We computed the contrast with the high-infiltrate areas. In fact, the latter are defined as those areas with high lymphocytic infiltrate, therefore where APM function is somehow preserved. The densities of the contrast show that almost all the probability mass fall below 0, indicating a substantial decrease in the probability of having that peculiar APM protein in that specific histotype

Fig. 4

Interpatient variability. The figure shows 10 realizations for each patient, for each TMA core and for each APM protein (i.e., the model representation of the data, with the advantage to show variability). Each column shows all the 126 patients, where the histotype is highlighted by the color and the core by the bending sites. The five columns are the APM protein tested. Cases that show greater uncertainty show more dispersed lines

Fig. 5

Kaplan–Meier plots for disease-free survival (DFS) and overall survival (OS) in APM proficient and deficient tumors