Metastatic breast cancer lesions immunologically depleted compared with primary

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.