Bolt Biotherapeutics, Redwood City, CA
Lisa K. Blum , Jason Ptacek , Heidi LeBlanc , William G. Mallet , Bruce A. Hug , Michael N. Alonso , Edith A. Perez , David Dornan , Marcin Kowanetz
Background: Immuno-oncology (IO) has historically focused on T cell-driven effects, but a growing class of myeloid therapies are under investigation. This class includes immune-stimulating antibody conjugates (ISACs), which comprise a tumor-targeting antibody conjugated to an immune-stimulating payload. ISACs may require both tumor-associated antigens and tumor-resident myeloid cells for activity. As new IO strategies such as TLR-activating ISACs are developed, understanding the myeloid landscape is relevant for cancer biology and drug development. Methods: Tumor microarrays with formalin-fixed paraffin embedded sections of breast (BC), colorectal (CRC), gastric (GC), head and neck squamous cell (HNSCC), and non-small cell lung (NSCLC) cancers were analyzed by immunohistochemistry for tumor antigens (HER2, CEA, PD-L1), myeloid cell markers (CD68/CD163/CD11c/BDCA2), and CD8+ T cells. Results: Tumor infiltrating myeloid cells and CD8+ T cells varied across indications (Table). Low densities of intra-tumoral CD8+ T cells (<100/mm2) were observed in CRC, with higher CD8+ T cell counts observed in other cohorts. In contrast to T cells, substantial myeloid infiltrates were observed across tumor types. While MSI status was associated with higher CD8+ T cell infiltration in CRC, myeloid cells were abundant in both MSI and MSS samples. Monocyte-derived (mDC) and conventional DCs (cDC), which respond strongly to TLR activation, were present in all indications, with highest numbers observed in NSCLC. HER2+ BC samples had high infiltration of plasmacytoid DCs, a key TLR7-responsive population. PD-L1 expression on immune cells was associated with higher CD8+ T cell and myeloid cell numbers. In contrast to HER2 and PD-L1, CEA expression was independent of immune infiltration. Conclusions: Abundant myeloid infiltrates were observed across solid tumors, independent of T-cell infiltration. The presence of myeloid cells in multiple tumor types offers broadscale therapeutic targets for ISACs and other myeloid-directed therapies that can activate the innate immune system as a bridge to adaptive immunity.
N | CD8+ cells | Macrophages (CD68+BDCA2- or CD163+CD11c-BDCA2-) | cDC & mDCs (CD11c+ CD68- BDCA2-) | Plasmacytoid DCs (BDCA2+ CD68- CD163-) | |
---|---|---|---|---|---|
CRC: Total | 245 | 99 (23, 228) | 217 (84, 493) | 50 (19, 193) | 12 (4, 33) |
CRC: MSI-L/H | 38 | 224 (92, 405) | 283 (132, 492) | 41 (16, 210) | 9 (4, 21) |
CRC: MSS | 157 | 68 (22, 187) | 217 (98, 429) | 49 (17, 171) | 12 (4, 35) |
BC: Total | 178 | 140 (41, 384) | 398 (215, 723) | 96 (41, 215) | 11 (4, 70) |
BC: HER2+ | 37 | 212 (116, 780) | 241 (166, 403) | 20 (5, 62) | 1423 (665, 2392) |
BC: Triple Negative | 70 | 187 (31, 593) | 699 (346, 1117) | 93 (44, 234) | 10 (3, 31) |
NSCLC | 74 | 207 (74, 510) | 549 (324, 787) | 445 (246, 861) | 7 (4, 17) |
HNSCC | 74 | 223 (77, 626) | 585 (311, 879) | 166 (59, 353) | 9 (3, 20) |
GC | 98 | 109 (31, 473) | 434 (234, 659) | 204 (80, 339) | 8 (5, 17) |
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