Location of tumor affects local and distant immune cell type and number

Abstract

IntroductionTumors comprise heterogeneous populations of cells, including immune infiltrates that polarize during growth and metastasis. Our preclinical studies on breast cancer (BCa) identified functional differences in myeloid‐derived suppressor cells based on tumor microenvironment (TME), prompting variations in host immune response to tumor growth, and dissemination based on tissue type.MethodsIn order to understand if such variations existed among other immune cells, and if such alteration occurs in response to tumor growth at the primary site or due to bone dissemination, we characterized immune cells, examining localized growth and in the tibia. In addition, immune cells from the spleen were examined from animals of both tumor locations by flow cytometry.ResultsThe study demonstrates that location of tumor, and not simply the tumor itself, has a definitive role in regulating immune effectors. Among all immune cells characterized, macrophages were decreased and myeloid dendritic cell were increased in both tumor locations. This difference was more evident in subcutaneous tumors. Additionally, spleens from mice with subcutaneous tumors contained greater increases in both macrophages and myeloid dendritic cells than in mice with bone tumors. Furthermore, in subcutaneous tumors there was an increase in CD4+ and CD8+ T‐cell numbers, which was also observed in their spleens.ConclusionsThese data indicate that alterations in tumor‐reactive immune cells are more pronounced at the primary site, and exert a similar change at the major secondary lymphoid organ than in the bone TME. These findings could provide translational insight into designing therapeutic strategies that account for location of metastatic foci.

Mucosal HPV E6/E7 Peptide Vaccination in Combination with Immune Checkpoint Modulation Induces Regression of HPV+ Oral Cancers

“…Although subcutaneous tumor models are a useful tool for rapid screening of potential interventions and generation of early mechanistic insights, robust preclinical evaluation of immunotherapeutics targeting HPV + malignancies requires their implantation in their natural mucosal environment (31, 32). As nearly half of oropharyngeal squamous cell carcinomas occur in the tongue (33), we investigated the two most efficacious immunomodulatory antibody combinations from our flank tumor studies (i.e., α4–1BB/αCD40 and α4–1BB/αCTLA-4) with or without HPV peptide vaccination against HPV + mEER tumors orthotopically implanted in the tongue.…”

“…We also observed that the combination of HPV vaccine with α4–1BB and αCD40 was highly effective for treating mEER tumors implanted subcutaneously but had limited efficacy against tongue tumors. The tumor microenvironment at these two locations may be comprised of distinct spectrums of immune cells and danger signals that may also affect the trafficking as well as functioning of immune cells (31, 32).…”

Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses

“…The cellular composition of the TME can also vary depending on the tissue of tumor growth. For example, in a murine model of breast cancer, the immune cell profile was compared between 4T1 tumors growing SC or intratibially ( 63 ). FACS analysis in this model revealed differences in the proportions of macrophages, DCs, CD8 + , and CD4 + T cells in the tibia and under the skin of mice with tumors growing at these sites.…”

Characterization of immune cell subtypes in three commonly used mouse strains reveals gender and strain-specific variations

“…In mice, bone marrow and spleen are two major hematopoietic organs 5, 6 . Although various immune cell subsets from these organs are commonly evaluated in studies, there is a lack of strain- and gender-specific benchmarks for each leukocyte cell subtype for these organs in healthy mice 7–9 .…”