Transferable anticancer innate immunity in spontaneous regression/complete resistance mice

Area of Science:

• Immunology
• Cancer Biology
• Innate Immunity

Background:

• Spontaneous regression/complete resistance (SR/CR) mice demonstrate a unique ability to resist lethal doses of cancer cells, unlike wild-type (WT) mice.
• The mechanisms underlying this innate cancer resistance in SR/CR mice remain incompletely understood.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms responsible for the innate resistance to cancer observed in SR/CR mice.
• To investigate the role of leukocyte infiltration and specific immune cell subsets in mediating cancer cell destruction.

Main Methods:

• Analysis of leukocyte infiltration into tumors in SR/CR mice following primary and repeated cancer cell challenges.
• In vitro killing assays using purified natural killer cells, neutrophils, and macrophages from SR/CR mice against cancer cells.
• Experimental depletion of specific leukocyte subsets in vivo to assess their contribution to resistance.
• Adoptive transfer experiments using SR/CR splenocytes, bone marrow cells, or peritoneal macrophages into WT recipient mice.

Main Results:

• SR/CR mice exhibit rapid infiltration of leukocytes, primarily of innate immunity, which is crucial for cancer resistance.
• Formation of rosettes between infiltrating leukocytes (natural killer cells, neutrophils, macrophages) and cancer cells precedes cancer cell destruction via cytolysis.
• Purified natural killer cells, macrophages, and neutrophils from SR/CR mice independently exhibit potent cancer cell-killing activity in vitro.
• Complete abrogation of resistance occurred upon depletion of all infiltrating leukocytes, but not when only one or two subsets were depleted.
• Resistance was transferable to WT mice via SR/CR splenocytes, bone marrow cells, or peritoneal macrophages, conferring protection against subsequent challenges or eradicating established tumors.

Conclusions:

• Innate immune cell infiltration, particularly of natural killer cells, neutrophils, and macrophages, is the primary mechanism driving spontaneous cancer resistance in SR/CR mice.
• The combined action of multiple innate immune cell types, rather than a single subset, is essential for effective cancer cell elimination.
• The resistance phenotype is transferable, suggesting the potential for immunotherapeutic strategies leveraging these innate immune mechanisms for cancer treatment.