Tumor-infiltrating lymphocyte abundance and programmed death-ligand 1 expression in metaplastic breast carcinoma: implications for distinct immune microenvironments in different metaplastic components

Abstract

Both stromal tumor-infiltrating lymphocytes (sTILs) and programmed death-ligand 1 (PD-L1) affect responses to immunotherapy; however, the extent of sTIL and PD-L1 expression within various metaplastic components in metaplastic breast carcinoma (MBC), which are critical for the characterization of immune microenvironments, remains unreported. We profiled sTIL infiltration and PD-L1 expression in different metaplastic components of specimens from 82 MBC patients. The overall positivity for high or intermediate (H/I) sTIL, immune cell-PD-L1 (IcPD-L1), and tumor cell-PD-L1 (TcPD-L1) was 34.1%, 47.6%, and 17.1%, respectively, but differences specific to MBC subtypes and each metaplastic component existed. Squamous cell carcinoma exhibited the highest positivity rates of sTIL(H/I) (50.0%) and IcPD-L1 (66.7%), while matrix-producing carcinoma had the lowest respective rates (14.3% and 28.6%). The positivity rates of sTIL(H/I) and IcPD-L1 were the highest in squamous component (Sq) and the lowest in chondroid component (Ch). All cases that had discordant sTIL categories between carcinoma of no special type (NST) and metaplastic components showed sTIL(H/I) positivity higher in Sq, but lower in spindled component (Sp) and Ch. While there was no pattern of higher IcPD-L1-positivity in Sp, six of the seven cases that were TcPD-L1-discordant between NST and Sp were TcPD-L1-positive in Sp, suggesting a trend for higher TcPD-L1 in Sp. The diagnostic predictability of total tumor IcPD-L1 positivity based on IcPD-L1 positivity in Sq and Ch was 95.2% and 33.3%, respectively. Multivariate analysis showed that sTIL(H/I) positivity, but not PD-L1 positivity, correlated with better survival. Our data implicate distinct immune microenvironments in different metaplastic components in MBC, which may have immunopathologic, diagnostic, and therapeutic significance.

Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma

“…Chao et al [ 134 ] found sqCC MBC exhibiting most TILs of all the MBC subtypes. Similarly, Lien et al [ 138 ] reported that sqCC exhibited the highest positivity rate of TILs, while matrix-producing carcinoma had the lowest. Kalaw et al [ 135 ] did not observe significant association between TILs and morphological subtypes of MBCs but observed that PD-L1 positive TILs were enriched in squamous cell carcinomas.…”

“…In contrast, no significant difference in the expression of PD-L1 in stromal cells was found among different types of tumors [ 133 , 135 , 137 ] (see Table 1 ). Additionally, no differences in PD-L1 expression in tumor cells were observed among different subtypes of MBC [ 135 , 138 ]. Lien et al [ 138 ] reported an increase of PD-L1 expression in immune cells of MBC with squamous differentiation.…”

“…Additionally, no differences in PD-L1 expression in tumor cells were observed among different subtypes of MBC [ 135 , 138 ]. Lien et al [ 138 ] reported an increase of PD-L1 expression in immune cells of MBC with squamous differentiation.…”

“…There is controversy regarding the association between TILS and longer disease-free survival in MBCs. Chao et al [ 134 ] and Chien et al [ 138 ] found a relationship between a greater number of TILS and longer disease-free survival, but Kalaw et al [ 135 ] found that TILs content did not significantly impact BC-specific survival in their MBC cohort. The latter authors observed that an increased amount of FOXP3 positive intra-tumoral TILs was associated with an adverse prognostic outcome [ 135 ].…”

An Update on the Molecular Pathology of Metaplastic Breast Cancer

“…staining in ≥1% tumor cells; ≥5% staining in peri-tumoral regions 38% tumor cell; 48% tumor immune microenvironment Morgan et al 62 2020 146 TNBC (27 MpBC) SP263 Memb. staining in ≥1% of tumor cells; immune cells MpBC 30% tum, 73% immune; TNBC 10% tum, 59% immune Afkhani et al 49 2019 14 MpBC SP263 >1+ intensity in >1% immune cells 50% immune cells Lien et al 63 2020 82 MpBC SP142 % tumor cells; immune cells as % of tumor area 17% tum; 48% immune cell Kalaw et al 64 2020 125 MpBC E1L3N ≥5% tumor/immune cells displaying cyto. or memb.…”