Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8⁺ and CD4⁺ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3^−/− mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner.

Immunogenic cell death (ICD) can switch immunologically “cold” tumors “hot”, making them sensitive to immune checkpoint inhibitor (ICI) therapy. Many therapeutic platforms combine multiple modalities such as oncolytic viruses (OVs) and low-dose chemotherapy to induce ICD and improve prognostic outcomes. We previously detailed many unique properties of oncolytic bovine herpesvirus type 1 (oBHV) that suggest widespread clinical utility. Here, we show for the first time, the ability of oBHV monotherapy to induce bona fide ICD and tumor-specific activation of circulating CD8⁺ T cells in a syngeneic murine model of melanoma. The addition of low-dose mitomycin C (MMC) was necessary to fully synergize with ICI through early recruitment of CD8⁺ T cells and reduced infiltration of highly suppressive PD-1⁺ Tregs. Cytokine and gene expression analyses within treated tumors suggest that the addition of MMC to oBHV therapy shifts the immune response from predominantly anti-viral, as evidenced by a high level of interferon-stimulated genes, to one that stimulates myeloid cells, antigen presentation and adaptive processes. Collectively, these data provide mechanistic insights into how oBHV-mediated therapy modalities overcome immune suppressive tumor microenvironments to enable the efficacy of ICI therapy.

Breast reconstruction after mastectomy improves the quality of life for many patients with breast cancer. There is uncertainty regarding eligibility criteria for reconstruction, timing (immediate or delayed—with or without radiotherapy), outcomes of nipple-sparing compared to skin-sparing mastectomy, selection criteria and surgical factors influencing outcomes of nipple-sparing mastectomy, prepectoral versus subpectoral implants, use of acellular dermal matrix, and use of autologous fat grafting. We conducted a systematic review of these topics to be used as the evidence base for an updated clinical practice guideline on breast reconstruction for Ontario Health (Cancer Care Ontario). The protocol was registered on PROSPERO, CRD42023409083. Medline, Embase, and Cochrane databases were searched until August 2024, and 229 primary studies met the inclusion criteria. Most studies were retrospective non-randomized comparative studies; 5 randomized controlled trials were included. Results suggest nipple-sparing mastectomy is oncologically safe, provided there is no clinical, radiological, or pathological indication of nipple-areolar complex involvement. Surgical factors, including incision location, may affect rates of complications such as necrosis. Both immediate and delayed reconstruction have similar long-term outcomes; however, immediate reconstruction may result in better short to medium-term quality of life. Evidence on whether radiotherapy should modify the timing of initial reconstruction or expander-implant exchange was very limited; studies delayed reconstruction after radiotherapy by at least 3 months and, more commonly, at least 6 months to avoid the period of acute radiation injury. Radiation after immediate reconstruction is a reasonable option. Surgical complications are similar between prepectoral and dual-plane or subpectoral reconstruction; prepectoral placement may give a better quality of life due to lower rates of long-term complications such as pain and animation deformity. Autologous fat grafting was found to be oncologically safe; its use may improve quality of life and aesthetic results.

Several postmastectomy breast reconstruction techniques and procedures have been implemented, although with limited evaluation of benefits and adverse effects. We conducted a systematic review on the plane and timing of reconstruction, and on the use of nipple-sparing mastectomy, acellular dermal matrix, and autologous fat grafting as the evidence base for an updated clinical practice guideline on breast reconstruction for Ontario Health (Cancer Care Ontario). Both immediate and delayed reconstruction may be considered, with preferred timing depending on factors such as patient preferences, type of mastectomy, skin perfusion, comorbidities, pre-mastectomy breast size, and desired reconstructive breast size. Immediate reconstruction may provide greater psychological or quality of life benefits. In patients who are candidates for skin-sparing mastectomy and without clinical, radiological, and pathological indications of nipple-areolar complex involvement, nipple-sparing mastectomy is recommended provided it is technically feasible and acceptable aesthetic results can be achieved. Surgical factors including incision location are important to reduce necrosis by preserving blood supply and to minimize nerve damage. There is a role for both prepectoral and subpectoral implants; risks and benefits will vary, and decisions should be made during consultation between the patient and surgeons. In patients who are suitable candidates for implant reconstruction and have adequate mastectomy flap thickness and vascularity, prepectoral implants should be considered. Acellular dermal matrix (ADM) has led to an increased use of prepectoral reconstruction. ADM should not be used in case of poor mastectomy flap perfusion/ischemia that would otherwise be considered unsuitable for prepectoral reconstruction. Care should be taken in the selection and handling of acellular dermal matrix (ADM) to minimize risks of infection and seroma. Limited data from small studies suggest that prepectoral reconstruction without ADM may be feasible in some patients. Autologous fat grafting is recommended as a treatment for contour irregularities, rippling following implant-based reconstruction, and to improve tissue quality of the mastectomy flap after radiotherapy.