Perioperative Immunotherapy: Different Treatment Strategies to Multiply Therapy Effectiveness

Despite its potential usefulness in completely eliminating tumor cells, cancer immunotherapy is deployed to confront intact primary or metastatic disease. It will be easier for the immune system to clear a small number of residual cancer cells, once the immunosuppressive tumor microenvironment (TME) is gone, rather than to eliminate bulky tumors that have many pathological cells and multiple models of immune evasion [1]. Removal of primary cancer cells and their associated TME (which comprise suppressive leukocytes and immunomodulatory cytokines and chemokines) is expected to enhanced a productive antitumor immunity. The knowledge about how the immune system works is very useful for the development of these therapies, as it has been described that intratumoral CD8+ T cells have a rare and variable ability to recognize tumor antigens and to be tumor-reactive [2]. Therefore, elimination of these cells from the TME could be more favorable than expected.

Differences in how the tumor cells can shape the TME to induce a suppressive outcome. Hinshaw DC, et al. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019 Sep 15;79(18):4557-4566. doi: 10.1158/0008-5472.CAN-18-3962.

An effective cancer immunotherapy must break the local immune tolerance induced within the TME, leading to systemic immune responses that can eliminate disseminated disease both in metastatic locations as well as in cancer cell sanctuaries [3], which are organs or tissues where tumors cannot be targeted by commonly used cancer therapies. Although the main strategy for cancer treatment is still surgery, post-surgical recurrence and metastasis remain primary causes of patient mortality because the transient but acute immunosuppressive inflammation caused by the wound-healing response to surgery has been suggested to cause tumor progression and metastasis [4]. Furthermore, as the wound-healing gene signature is correlated with resistance to immune checkpoint blockade in the clinics, the perioperative setting represents an interesting context in which to administer immunotherapy in order to multiply the chances of treatment success. In an article published in 2017 [5], researchers took advantage of cells that naturally traffic to sites of inflammation and used them as an active delivery agents. They used a strategy based in the post-resection adoptive transference of mouse platelets to which anti programmed cell death protein 1 ligand 1 (PDL1) had been conjugated to promote the immunotherapy accumulation at the tumor resection site, thus reducing post-surgical recurrence and metastasis. Cargo was released when platelet become activated within the bound, and mice showed a relapse and prevention of melanoma and breast tumors, with a durable survival relative to unmodified platelets or free antibody treatments. 

Recent research has been focused on the development of macroscale delivery devices that can be used as deposits for local delivery of small biomolecules, immunomodulatory (either activating or inhibitory) agents, or even cells. The use of hydrogel-based scaffolds loaded with tumor-reactive artificial antigen-presenting cells (APCs) or T cells placed near or at tumor resection sites could promote the delivery, expansion and dispersion of tumor cell-targeting T cells [6]. In mice, this strategy was very effective when treating incompletely resected or inoperable orthotopic disease, where adoptive cell therapy lacking scaffolds failed to control the disease. Bearing in mind that a huge effort is needed to combine scaffolds with cell therapy, other studies are focused on the engineering of acellular protein-based hydrogels loaded with bioactive molecules. One strategy is based on the use of calcium carbonate nanoparticles containing anti-CD47 antibodies that can be sprayed in situ at the tumor resection site. CD47 is a surface marker often overexpressed on cancer cells that inhibit macrophage phagocytosis by engaging the inhibitory receptor signal regulatory protein α (SIRPα). Local administration of anti-CD47 will restore phagocytosis, thus priming adaptive antitumor responses [7]. Due to the fact that macrophages can be polarized to an M2 phenotype within TME, which contributes to local immunosuppression, anti-CD47 hydrogels can also be used to reprogram macrophages to an M1 like (proinflammatory) phenotype. Macrophages with an increased phagocytosis can serve as APCs to initiate T cell mediated responses.  

Perioperative immunotherapy can be used to control residual tumor cells after tumor resection. Goldberg MS. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer. 2019 Oct;19(10):587-602. doi: 10.1038/s41568-019-0186-9.

Another study suggested that placement, within the post-resection cavity, of hydrogels containing agonists of innate immunity such as cytokines that promotes lymphocyte effector function and small molecules that stimulate the production of type I IFN could be particularly useful in the context of complete resection [8]. The main advantage of hydrogels is that they allow the local and sustained release of bioactive molecules or cells, leading to a durable survival benefit that could not be achieved by delivery of the same components in solution. 

In the same article, researchers found that reprogramming the post resection microenvironment from immunosuppressive to immunostimulatory induced systemic antitumor immunity that led to the eradication of existing spontaneous metastases. Furthermore, even in extremely aggressive mouse models that otherwise have required combinations of up to 4 immunotherapies administered repeatedly, administration of a single hydrogel load with a single payload within the post-resection microenvironment yielded the desired antitumor activity. This is of capital importance because hydrogels improve both the efficacy due to the concentration of the effective dose at the target site, as well as the safety by limiting systemic exposure that can break peripheral tolerance. 

Surgery still remains as a standard and effective therapy for patients with solid tumors, and the translation of immunoengineering approaches such as cell-, cytokine- or bioactive molecules loaded hydrogels within the post-surgical microenvironment could be a promising approach to avoid post-surgical recurrence and metastasis. More efforts are needed to better understand the TME behavior and the mechanisms underlying tolerance and immune evasion, but we are close to the development of efficient combination of therapies to fight against complicated diseases.  


1. Spranger, S. and T.F. Gajewski, Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer, 2018. 18(3): p. 139-147.

2. Scheper, W., et al., Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med, 2019. 25(1): p. 89-94.

3. Marabelle, A., et al., Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest, 2013. 123(6): p. 2447-63.

4. Hiller, J.G., et al., Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol, 2018. 15(4): p. 205-218.

5. Wang, C., et al., In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nature Biomedical Engineering, 2017. 1(2): p. 0011.

6. Smith, T.T., et al., Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest, 2017. 127(6): p. 2176-2191.

7. Tseng, D., et al., Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A, 2013. 110(27): p. 11103-8.

8. Park, C.G., et al., Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. Sci Transl Med, 2018. 10(433).

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