Methods of enhancing immunity
The present invention is based on the finding that CD11b signaling inhibits immune suppression, modulates neovascularization and promotes anti-tumor immune responses in models of murine and human cancer. As such, provided herein are methods of treating cancer using an antibody, protein or small molecule that modulates CD11b activity or expression. Also provided are methods of identifying cancer that is amenable to such treatment and/or increasing susceptibility of cancer cells to treatment with a chemotherapeutic agent.
1. A method of identifying a cancer amenable to treatment with an agonist of CD11b or a Let7a miRNA comprising detecting expression levels of CD11b or Let7a miRNA in a sample comprising cancer associated myeloid cells from a subject, contacting the sample with an agonist of CD11b or a Let7a miRNA and detecting increased levels of CD11b or a Let7a miRNA, thereby identifying the cancer as being amenable to treatment with the agonist of CD11b or a Let7a miRNA.
2. The method of claim 1 , further comprising detecting an increase in expression of one or more of Arg1, Tgfb, 1110, 116 or Pdgfb after contacting with the inhibitor, as compared to expression prior to contacting.
3. The method of claim 1 , further comprising detecting a decrease in expression of one or more of Il12, Ifng, Nos2, or Tnfa after contacting with the inhibitor, as compared to expression prior to contacting.
4. A method of increasing susceptibility of a cancer cell of a subject to chemotherapeutic treatment comprising contacting cancer associated myeloid cells obtained from the subject with Let7a miRNA or leukadherin 1 (LA1), thereby increasing susceptibility of the cancer cell to chemotherapeutic treatment.
5. The method of claim 4 , wherein the chemotherapeutic treatment is administration of an agent selected from the group consisting of gemcitabine, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab.
6. A method of screening for a therapeutic agent for treating cancer, comprising administering a test agent to a transgenic non-human mammal whose genome comprises a mutation at Ile332 of exon 9 of the ITGAM gene, wherein the transgenic non-human mammal has the phenotype of loss of an Exon-9 Bgl II restriction site, and evaluating the effect of the test agent on at least one of expression levels of CD11b or Let7a in at least one disease-relevant tissue of the transgenic non-human mammal, wherein at least one of: an increase in the amount of CD11b expression, an increase in the amount of Let7a expression, or increase in the amount of CD11b expression and an increase in the amount of Let7a expression in at least one disease-relevant tissue relative to a similar transgenic non-human mammal that does not receive the test agent indicates the test agent is therapeutic for the cancer.
7. The method of claim 6 , further comprising detecting increases in expression of one or more of Il1b, Tnfa, Il12, Nos2 and Ifng in at least one disease-relevant tissue relative to a similar transgenic non-human mammal that does not receive the test agent, thereby confirming that the test agent is therapeutic for the cancer.
8. The method of claim 6 , wherein the Ile332 is substituted with Gly.
9. The method of claim 6 , wherein the mammal is a mouse.